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Guideline Summary
Guideline Title
VA/DoD clinical practice guideline for management of major depressive disorder (MDD).
Bibliographic Source(s)
Department of Veteran Affairs, Department of Defense. VA/DoD clinical practice guideline for management of major depressive disorder (MDD). Washington (DC): Department of Veteran Affairs, Department of Defense; 2009 May. 199 p.
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: VHA/DOD clinical practice guideline for the management of major depressive disorder in adults. Washington (DC): Department of Veterans Affairs (U.S.); 2000. Various p.

FDA Warning/Regulatory Alert

Note from the National Guideline Clearinghouse: This guideline references a drug(s) for which important revised regulatory and/or warning information has been released.

  • December 17, 2013 – Methylphenidate ADHD Medications External Web Site Policy: The U.S. Food and Drug Administration (FDA) is warning that methylphenidate products, one type of stimulant drug used to treat attention deficit hyperactivity disorder (ADHD), may in rare instances cause prolonged and sometimes painful erections known as priapism. Based on a recent review of methylphenidate products, FDA updated drug labels and patient Medication Guides to include information about the rare but serious risk of priapism. If not treated right away, priapism can lead to permanent damage to the penis.

Scope

Disease/Condition(s)

Major depressive disorder (MDD)

Guideline Category
Counseling
Diagnosis
Evaluation
Management
Risk Assessment
Screening
Treatment
Clinical Specialty
Emergency Medicine
Family Practice
Geriatrics
Internal Medicine
Pharmacology
Psychiatry
Psychology
Intended Users
Advanced Practice Nurses
Nurses
Physician Assistants
Physicians
Psychologists/Non-physician Behavioral Health Clinicians
Social Workers
Guideline Objective(s)
  • To reduce current practice variation and provide facilities with a structured framework to help improve patient outcomes
  • To provide evidence-based recommendations to assist providers and their patients in the decision-making process for patients with major depressive disorder (MDD)
  • To identify outcome measures to support the development of practice-based evidence that can ultimately be used to improve clinical guidelines
Target Population

Adult patients with major depressive disorder (MDD)

This guideline applies to patients presenting with symptoms of depression, and to patients being followed for major depressive disorder. (This includes those newly diagnosed, those receiving ongoing treatment, and those with chronic depression).

Note: The guideline does not cover the management of patients with minor depression or dysthymia and is limited to depression in adults only.

Interventions and Practices Considered

Screening/Diagnosis/Evaluation

  1. Screening patients using the Patient Health Questionnaire (PHQ) 2- and 9-item
  2. Assess if patient is at high risk of harm to self or others
  3. Medical history (psychiatric, marital, and family history)
  4. Physical examination including mental status examination
  5. Relevant laboratory tests (such as complete blood count [CBC], chemistry profile, thyroid status)
  6. Diagnostic work-up including review of all prescription and over-the-counter medications, vitamins, and herbals; review of comorbid conditions and unexplained symptoms

Management/Treatment

  1. Mental health referral or consultation
  2. Psychoeducation and self-management including patient education about the nature of depression, treatment options, and adherence to treatment
  3. Pharmacologic treatment
    • Selective serotonin reuptake inhibitors (SSRIs)
    • Serotonin norepinephrine reuptake inhibitors (SNRIs)
    • Bupropion
    • Mirtazapine
    • Tricyclic and tetracyclic antidepressants (TCAs)
    • Monoamine oxidase inhibitors (MAOIs)
    • Psychostimulants
  4. Psychotherapy
    • Cognitive behavioral therapy (CBT)
    • Interpersonal psychotherapy (IPT)
    • Problem-solving therapy (PST)
    • Behavior therapy/behavioral activation (BT/BA)
    • Couple/marital-focused therapies
    • Client-centered counseling
    • Psychodynamic therapy
  5. Somatic treatment including electroconvulsive therapy (ECT) and vagus nerve stimulation (VNS)
  6. Other treatments
Major Outcomes Considered
  • Sensitivity and specificity of screening tools
  • Effectiveness of treatment
    • Overall well-being
    • Suicide ideation
    • Occupational and social functioning
    • Remission rate
    • Relapse rate
  • Adverse effects of medications

Methodology

Methods Used to Collect/Select the Evidence
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Formulation of Questions

The Working Group developed researchable questions and associated key terms after orientation to the scope of the guideline and to goals that had been identified by the Working Group. The questions specified (adapted from the Evidence-Based Medicine toolbox, Centre for Evidence-Based Medicine, http://www.cebm.net External Web Site Policy):

  • Population – Characteristics of the target patient population
  • Intervention – Exposure, diagnostic, or prognosis
  • Comparison – Intervention, exposure, or control used for comparison
  • Outcome – Outcomes of interest

These specifications served as the preliminary criteria for selecting studies. Literature searches were conducted on all topics identified in the algorithm or recommendations of the original guidelines.

Selection of Evidence

The evidence selection was designed to identify the best available evidence to address each key question and ensure maximum coverage of studies at the top of the hierarchy of study types. Published, peer-reviewed randomized controlled trials (RCTs), as well as meta-analyses and systematic reviews that included randomized controlled studies, were considered to constitute the strongest level of evidence in support of guideline recommendations. This decision was based on the judgment that RCTs provide the clearest, most scientifically sound basis for judging comparative efficacy. The Working Group made this decision while recognizing the limitations of RCTs, particularly considerations of generalizability with respect to patient selection and treatment quality. When available, the search sought out critical appraisals already performed by others that described explicit criteria for deciding what evidence was selected and how it was determined to be valid. The sources that have already undergone rigorous critical appraisal include Cochrane Reviews, Best Evidence, Technology Assessment, and Agency for Healthcare Research and Quality (AHRQ) systematic evidence reports.

In addition to Medline/PubMed, the following databases were searched: Database of Abstracts of Reviews of Effectiveness (DARE) and Cochrane Central Register of Controlled Trials. For Medline/PubMed searches, limits were set for language (English), and type of research (RCT, systematic reviews, and meta-analysis).

As a result of the literature reviews, articles were identified for possible inclusion. These articles formed the basis for formulating the guideline recommendations. The following inclusion criteria were used for studies:

  • English language only of studies performed in United States, United Kingdom, Europe, Australia, Japan, New Zealand
  • Full articles only
  • Study populations age limited to adults greater than 18 years; all races, ethnicities, cultural groups
  • Randomized controlled trials or prospective studies
  • Key outcomes cited
  • Published from July 2000 to the end of 2006

Admissible evidence (study design and other criteria):

  • Original research studies that provide sufficient detail regarding methods and results to enable use and adjustment of the data and results.
  • Randomized controlled trials, systematic reviews (including evidence-based practice center [EPC] and health technology assessment [HTA] reviews), and meta-analyses.
  • Relevant outcomes must be able to be abstracted from data presented in the articles.
  • Sample sizes must be appropriate for the study question addressed in the paper. RCTs will be included only if they are initiated with 10 or more participants.
Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Weighting According to a Rating Scheme (Scheme Given)
Rating Scheme for the Strength of the Evidence

Quality of Evidence (QE)

I At least one properly done randomized controlled trial
II-1 Well-designed controlled trial without randomization
II-2 Well-designed cohort or case-control analytic study, preferably from more than one source
II-3 Multiple time series evidence with/without intervention, dramatic results of uncontrolled experiment
III Opinion of respected authorities, descriptive studies, case reports, and expert committees

Overall Quality (OQ)

Good High grade evidence (I or II-1) directly linked to health outcome
Fair High grade evidence (I or II-1) linked to intermediate outcome
or
Moderate grade evidence (II-2 or II-3) directly linked to health outcome
Poor Level III evidence or no linkage of evidence to health outcome

Net Effect of Intervention

Substantial More than a small relative impact on a frequent condition with a substantial burden of suffering, or
A large impact on an infrequent condition with a significant impact on the individual patient level
Moderate A small relative impact on a frequent condition with a substantial burden of suffering, or
A moderate impact on an infrequent condition with a significant impact on the individual patient level
Small A negligible relative impact on a frequent condition with a substantial burden of suffering, or
A small impact on an infrequent condition with a significant impact on the individual patient level
Zero or Negative Negative impact on patients, or
No relative impact on either a frequent condition with a substantial burden of suffering, or
An infrequent condition with a significant impact on the individual patient level

 

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review with Evidence Tables
Description of the Methods Used to Analyze the Evidence

Preparation of Evidence Tables (Reports) and Evidence Rating

The results of the search were organized and evidence reports, as well as copies of the original studies, were provided to the Working Group for further analysis. Each reference was appraised for scientific merit, clinical relevance, and applicability to the populations served by the Federal healthcare system. Recommendations were based on consensus of expert opinions and clinical experience only when scientific evidence was unavailable.

A group of research analysts read and coded each article that met inclusion criteria. The articles have been assessed for methodological rigor and clinical importance.

Recommendation and Overall Quality Rating

Evidence-based practice involves integrating clinical expertise with the best available clinical evidence derived from systematic research. The Working Group received an orientation and tutorial on the U.S. Preventive Service Task Force (USPSTF) 2001 evidence rating process, reviewed the evidence and independently formulated Quality of Evidence ratings, a rating of Overall Quality (see the "Rating Scheme for the Strength of the Evidence" field), and a Strength of Recommendation (see the "Rating Scheme for the Strength of the Recommendation" field).

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

Guideline Development Process

The development update of the Department of Veterans Affairs/Department of Defense (VA/DoD) Clinical Practice Guideline for Management of Major Depressive Disorder (MDD) followed the steps described in "Guideline for Guidelines," an internal working document of the VA/DoD Evidence Based Practice Working Group, that requires an ongoing review of the work in progress. The Working Group of the VA/DoD was charged to update the evidence-based action recommendations whenever possible.

The Offices of Quality and Performance and Patient Care Services, in collaboration with the network Clinical Managers, the Deputy Assistant Under Secretary for Health, and the Medical Center Command of the DoD identified clinical leaders to champion the guideline development process. During a preplanning conference call, the clinical leaders defined the scope of the guideline and identified a group of clinical experts from the VA and DoD that formed the Management of MDD Working Group. Working Group members included internists, family practitioners, psychiatrists, psychologists, psychiatric nurses, and social workers, from a wide variety of specialty and primary care settings, diverse geographic regions, and both VA and DoD health care systems.

The Working Group defined a set of clinical questions within the area of the guideline. This ensured that the guideline development work outside the meeting focused on issues that practitioners considered important and produced criteria for the search and the protocol for systematic review and, where appropriate, meta-analysis.

The Working Group participated in an initial face-to-face meeting to reach consensus about the guideline algorithm and recommendations and to prepare a draft update document. The draft continued to be revised by the Working Group through numerous conference calls and individual contributions to the document. Following the initial effort, an editorial panel of the Working Group convened to further edit the draft document. Recommendations for the performance or inclusion of specific procedures or services were derived through a rigorous methodological approach that included the following:

  • Determining appropriate criteria, such as effectiveness, efficacy, population benefit, or patient satisfaction
  • Reviewing literature to determine the strength of the evidence in relation to these criteria
  • Formulating the recommendations and grading the level of evidence supporting the recommendation

This update of the MDD Guideline is the product of many months of diligent effort and consensus building among knowledgeable individuals from the VA, DoD, and academia, as well as guideline facilitators from the private sector. An experienced moderator facilitated the multidisciplinary Working Group.

Lack of Evidence – Consensus of Experts

Where existing literature was ambiguous or conflicting, or where scientific data was lacking on an issue, recommendations were based on the clinical experience of the Working Group.

Rating Scheme for the Strength of the Recommendations

Final Grade of Recommendation

  The net benefit of the intervention
Quality of Evidence Substantial Moderate Small Zero or
Negative
Good A B C D
Fair B B C D
Poor I I I I

Evidence Rating System

A A strong recommendation that the clinicians provide the intervention to eligible patients.
Good evidence was found that the intervention improves important health outcomes and concludes that benefits substantially outweigh harm.
B A recommendation that clinicians provide (the service) to eligible patients.
At least fair evidence was found that the intervention improves health outcomes and concludes that benefits outweigh harm.
C No recommendation for or against the routine provision of the intervention is made.
At least fair evidence was found that the intervention can improve health outcomes, but concludes that the balance of benefits and harms is too close to justify a general recommendation.
D Recommendation is made against routinely providing the intervention to asymptomatic patients.
At least fair evidence was found that the intervention is ineffective or that harms outweigh benefits.
I The conclusion is that the evidence is insufficient to recommend for or against routinely providing the intervention.
Evidence that the intervention is effective is lacking, or poor quality, or conflicting, and the balance of benefits and harms cannot be determined.
Cost Analysis

Published cost-effectiveness analyses were reviewed.

Method of Guideline Validation
Peer Review
Description of Method of Guideline Validation

Experts from the Veterans Administration (VA) and the Department of Defense (DoD) reviewed the final draft, and their feedback was integrated into the final draft document. The final document has been approved by all members of the Working Group.

Recommendations

Major Recommendations

The recommendations for the management of major depressive disorder (MDD) are presented in the form of three algorithms and annotations. The algorithms describe the step-by-step process of clinical decision-making and intervention that should occur when managing patients with MDD. General and specific recommendations for each step in the algorithms are included in an annotation section following the algorithms. The quality of evidence (QE) grading (I-III); overall quality (Good, Fair, Poor); and final grade of recommendations (SR) (A-D, I) are provided for specific statements. These grades, along with "net effect of the interventions" are defined at the end of the "Major Recommendations" field.

  1. Definitions

    Diagnosis of MDD

    MDD diagnosis is based on the following list of symptoms, and requires the presence of symptom 1, 2, or both; and at least 5 of 9 symptoms overall; these symptoms must persist for at least 2 weeks.

    1. Depressed mood nearly every day for most of the day, based on self-report or observation of others
    2. Marked reduction or loss of interest or pleasure in all, or nearly all, activities for most of the day, nearly every day
    3. Significant non-dieting weight loss or weight gain (>5% change in body weight)
    4. Insomnia or hypersomnia nearly every day
    5. Psychomotor agitation or retardation (should be observable by others)
    6. Fatigue/loss of energy nearly every day
    7. Feelings of worthlessness or excessive/inappropriate guilt (possibly delusional) nearly every day
    8. Diminished cognitive function (reduced ability to think or concentrate, or indecisiveness) nearly every day
    9. Recurrent thoughts of death and/or suicide, suicide planning, or a suicide attempt
  1. Screening

    Screening Adults

    Action Statement

    Identify patients who are depressed and are no longer engaged in treatment.

    Recommendations

    1. The Patient Health Questionnaire (PHQ) 2-item should be completed annually by all patients seen in primary care settings. [A]
    2. Patients who screen positive on the PHQ 2-item should have both a documented assessment using a quantitative questionnaire to further assess whether the patient has sufficient symptoms to warrant a diagnosis of clinical major depression and a full clinical interview that includes evaluation for suicide risk. [B]
    3. In patients at particularly high risk for depression based on medical illness (e.g., hepatitis C starting interferon treatment or post-myocardial infarction), clinicians should have a high index of suspicion for depression and use a diagnostic assessment tool (e.g., Patient Health Questionnaire 9-item) when depression is suspected. [I]
    4. Caution should be used in screening patients older than 75 years since screening instruments may not perform as well as in patients 65 to 75 years old. [C]

    See Appendix B: Screening and Assessment Instruments in the original guideline.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Two-item screens based on the PHQ have good sensitivity in mid-life, postpartum women, and older patients Kroenke, Spitzer, & Williams, 2003; Whooley et al., 1997; Williams et al., 2002 I Good A
    Studies targeting or including elderly patients Arroll, Khin, & Kerse, 2003 I Fair B
    Blank, Gruman, & Robison, 2004 II
    Corson, Gerrity, & Dobscha, 2004 II
    Kroenke, Spitzer, & Williams, 2003 II
    Li et al., 2007 II
    Whooley et al., 1997 I
    Studies done with VA patients Corson, Gerrity, & Dobscha, 2004 II Fair B
    Whooley et al., 1997 I
    2 Studies in postpartum patients Kroenke, Spitzer, & Williams, 2003 II Fair B
    3 Two-item screens perform better than single item screens addressing mood only Alessi et al., 2003; Blank, Gruman, & Robison, 2004; Corson, Gerrity, & Dobscha, 2004 II Fair B
    4 Depression questionnaires, including longer instruments such as the GDS, may not perform as well in individuals > 75 years old Watson et al., 2004 II Fair C
    5 Screening should be done annually Working Group Consensus III Poor I

    GDS, Geriatric Depression Scale; PHQ, Patient Health Questionnaire; QE, quality of evidence; SR, strength of recommendation; VA, Veterans Affairs

    Screening/Assessment for Depression in Pregnancy and in the Postpartum Period

    Action Statement

    Identify women who are depressed during pregnancy or in the postpartum period.

    Recommendations

    1. Women should be screened for depression at their first contact with healthcare services in both the antenatal and the postnatal periods. [B]
    2. Depression screening should be performed with either the Edinburgh Postnatal Depression Scale (EDPS) or the PHQ-2. [B]
    3. In the postpartum period, recommended screening is typically at 4 to 6 weeks and 3 to 4 months. [C]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Women are at increased risk for depressive disorders during pregnancy and postpartum periods Gaynes et al., 2005 I Good A
    2 Depression screening improves detection during pregnancy and during the postpartum period Georgiopoulos et al., 2001; Gjerdingen & Yawn, 2007; National Collaborating Centre for Mental Health, 2004 I Good B
    3 PHQ-2 is a sensitive screen for depression in postpartum women Kroenke, Spitzer, & Williams, 2003 II Fair B
    Spitzer et al., 2000 I
    4 Edinburgh Postnatal Depression Scale (EDPS) is a sensitive and valid screen for depression in the antepartum and postpartum period Adouard, Glangeaud-Freudenthal, & Golse, 2005; Evins, Theofrastous, & Galvin, 2000; Peindl, Wisner, & Hanusa, 2004; Boyd, Le, & Somberg, 2005 II Good B

    PHQ, Patient Health Questionnaire; QE, quality of evidence; SR, strength of recommendation

Annotation B. Brief Assessment of Initial Presentation to Assess for Dangerousness

  1. Dangerous Conditions

    Assess for Dangerousness

    Action Statement

    Identify patients who are at high risk of harm to self or others.

    Recommendations

    1. A referral to emergency services and/or consultation with a mental health professional is indicated for patients presenting with any of the following unstable conditions:
      • Delirium
      • Marked psychotic symptoms
      • Severe depressive symptoms/depression (e.g., catatonia, malnourishment, severe disability)
      • Suicidality or homicidality
      • Potential for violence (e.g., ideas about or intent to harm others; history of violent behavior; severe agitation or hostility; active psychosis)
      • Substance withdrawal or intoxication
    1. Any patient with suicidal ideation or attempts necessitating psychiatric hospitalization should be considered for referral to mental health specialty care.

    For more information on these conditions see: Appendix C: 'Suicidality' in the original guideline.

Annotation C. Unstable Urgent Condition?

Is Patient a Threat to Self or Others?

Action Statement

Identify patients who pose a threat to self or others and initiate appropriate intervention.

Recommendations

  1. Patients with a presumptive diagnosis of MDD should be assessed for suicidality by using a direct line of questioning. One recommended line of questioning uses the following (modified from Hirschfeld & Russell, 1997):
    • "Have you had thoughts about death or about killing yourself?"
    • "Tell me about your hopes for the future."
    • "Do you have a plan for how you would kill yourself?"
    • "Are there means available (e.g., pills, a gun and bullets, or poison)?"
    • "Have you actually rehearsed or practiced how you would kill yourself?"
    • "Do you tend to be impulsive?"
    • "How strong is your intent to do this?"
    • "Can you resist the impulse to do this?"
    • "Have you heard voices telling you to hurt or kill yourself?"
    • Ask about previous attempts, especially the degree of intent.
    • Ask about suicide of family members or significant others.
  1. Risk of violence towards others should be assessed by asking directly whether or not the patient has thoughts of harming anyone:
    • Assess whether the patient has an active plan and method/means (e.g., weapons in the home)
    • Assess whom the patient wishes to harm
    • Assess whether the patient has ever lost control and acted violently
    • Assess seriousness/severity of past violent behavior
  1. In the event of expressed dangerousness to self or others by a person with possible MDD, steps must be taken to insure patient safety until further evaluation and a referral or consultation with a mental health professional has taken place.

Evidence Table

  Evidence Source QE Overall Quality SR
1 Suicide risk factors and related conditions U.S. Preventive Services Task Force (USPSTF), 1996 I Fair B

QE, quality of evidence; SR, strength of recommendation

Is There Evidence of Psychosis?

Action Statement

Identify patients who have acute or chronic psychosis and treat accordingly.

Recommendations

  1. Patients with a possible diagnosis of MDD should be assessed for acute or chronic psychosis.
  2. Patients with a possible diagnosis of MDD who exhibit any of the following characteristics related to psychosis need to be referred for urgent/emergent mental health intervention as these are inappropriate for care in the primary care setting:
    • Serious delusions (e.g., fixed false beliefs)
    • Visual or (typically) auditory hallucinations
    • Confusion (incoherence)
    • Catatonic behavior (e.g., motoric immobility or excessive agitation)
    • Extreme negativism or mutism
    • Peculiar voluntary movement
    • Inappropriate effect of a bizarre or odd quality
  1. Patients who have longstanding psychotic illness and who are able to attend to present circumstances without responding to their psychosis may be evaluated and treated for a comorbid depression in the primary care setting.

Annotation D. Provide Appropriate Care or Refer to Stabilize and Follow Legal Mandates

Provide Appropriate Care or Refer to Stabilize and Follow Legal Mandates

Action Statement

Ensure that appropriate care, protocols and regulatory/policy mandates are followed during diagnosis and stabilization of the patient with MDD with an unstable condition.

Recommendations

  1. Local, state, and federal regulations/mandates as well as guidelines should be followed if the patient represents a risk to self or others.
  2. In managing patients who pose a risk, mental health providers need to be prepared to consult with primary care and other medical specialties concerning patients who may be encountered in their clinics.
  3. Patient care management plans must reflect the realities of local resources, staffing, and transportation.
  4. Consultation with a peer and/or medical law consultant on the legal and ethical requirements is recommended as it relates to notifications regarding the patient who represents a risk to others.

Annotation E. Obtain Relevant History, Physical Examination and Laboratory Tests; Obtain Symptom Score Using PHQ-9; Determine and Document Diagnostic and Statistical Manual of Mental Disorders, 4th Edition Text Revision (DSM-IV-TR) Criteria for MDD

  1. Assessment

    Obtain History, Physical Examination and Laboratory Tests

    Action Statement

    Complete a thorough medical and mental health history and examination to develop an appropriate clinical understanding of the patient's condition and arrive at a diagnosis.

    Recommendations

    1. Once the patient is stable, the clinical assessment should be completed by the primary care provider, including a relevant history, physical examination, and laboratory tests as indicated. [I]
    2. Relevant history may include the following:
      • Review of the impact of depressive symptoms on functional status. Typical questions include:
        • "During the past few weeks, have any physical or emotional problems interfered with your typical daily activities?"
        • "Has it been more difficult to do things on your own or with your (family, friends, neighbors, church, etc.)?"
        • If positive, areas for brief inquiry include: job, pleasurable hobbies, social activities, and important personal relationships.
      • Review of psychiatric, marital, family, and military service history, past physical or sexual abuse, and medication or substance use.
      • Treatment for any prior mental health problems, past psychiatric hospitalizations, or inability to function in usual life roles.
      • Additional information to the PHQ-9 that may help diagnose depression and determine severity of symptoms, such as:
        • Medically unexplained physical symptoms
        • Chronic, debilitating medical conditions
        • Current substance abuse/use
        • Decrease in sensory, physical, or cognitive function
        • Victim of current or past physical or sexual abuse or emotional neglect
        • Family history of major depression
        • Loss of significant relationship, primary support system, or economic status
        • Neurological disorder (e.g., multiple sclerosis, Parkinson's disease, stroke) or history of closed head injury
        • Protracted care-giving role for a family member with a chronic, disabling condition
        • Spousal bereavement and widowhood
        • Symptoms or signs of post traumatic stress disorder
        • Mania/hypomania
      • Review of medications, including prescription drugs and over-the-counter drugs (herbals, nutritionals, vitamins, and body building supplements).
    1. Physical examination
      • Appropriate physical examination including mental status exam; in certain subpopulations (e.g., elderly, traumatic brain injury), a screen for cognitive impairment is appropriate.
    1. Laboratory tests as clinically indicated, e.g., complete blood count (CBC), chemistry profile, thyroid studies, B12 and folate assessments, pregnancy screen and toxicology screen and an electrocardiogram (ECG) for patients over the age of 40.

    Symptom Score (PHQ-9)

    Action Statement

    Use a standardized instrument (PHQ-9) to document baseline depressive symptoms, measure symptom severity, and assist in evaluating treatment response and future progress.

    Recommendations

    1. For patients with a positive depression screen or in whom depression is suspected, administer the PHQ-9 as a component of the initial assessment. [B]
    2. DSM-IV-TR criteria should be used to diagnose depression. The PHQ-9 assessment tool combined with a clinical interview should be used to obtain the necessary information about symptoms, symptom severity, and effects on daily functioning that is required to diagnose MDD based on DSM-IV-TR criteria.
    3. The PHQ-9 should be used to monitor treatment response at 4 to 6 weeks, after each change in treatment, and to periodically assess the patient's response to treatment until full remission is achieved.

    (See Appendix B: 'Screening and Assessment Instruments' in the original guideline document).

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Depression questionnaires are useful for identifying major depressive disorder and dysthymic disorder Williams et al., 2002 I Good A
    2 PHQ-9 performed better than other self-administered instruments for identifying major depressive disorder Henkel et al., 2003; Kroenke, Spitzer, & Williams, 2001; Löwe et al., "Diagnosing," 2004; Williams et al., 2002 I Good B
    3 PHQ-9 is responsive to change in clinical status Löwe et al., "Monitoring," 2004 II Fair A
    4 Systematic assessment of treatment response is a component of efficacious primary care treatment models Bower et al., 2006; Gilbody et al., 2006; Williams et al., 2007 I Good A

    PHQ, Patient Health Questionnaire; QE, quality of evidence; SR, strength of recommendation

Annotation F. Do Medications or Comorbid Medical Conditions Contribute to Symptoms?

  1. Diagnostic Work-Up

    Do Medications Cause or Contribute to Symptoms?

    Action Statement

    Identify patients who may be experiencing depressed symptoms as a side effect of medication.

    Recommendations

    1. The diagnostic work-up for MDD should include a review of all prescription or over-the-counter (OTC) medications as they may cause or contribute to the depressive symptoms.
    2. Consideration should also be given to herbals, nutritionals, vitamins, and body building supplements, particularly when consumed in large doses.
    3. Consider discontinuing the offending medication as clinically indicated.

    Common medications that contribute to or may cause depressive symptoms are presented in Table 3 in the original guideline document.

    Do Medical Conditions Contribute to Symptoms?

    Action Statement

    Identify patients who may be experiencing depressed symptoms as a result of an underlying medical condition.

    Recommendations

    1. The diagnostic work-up for MDD should include evaluation for existing or emerging medical conditions that may exacerbate the depression. These may include:
      • Cardiovascular diseases
      • Chronic pain syndrome
      • Degenerative diseases
      • Immune disorders
      • Metabolic endocrine conditions (including kidney and lung diseases)
      • Neoplasms
      • Trauma
    1. Simultaneous treatment is often required for both the medical problem and psychiatric symptoms and can lead to overall improvement in function.

    Table 4 in the original guideline document includes many of the pathobiologies associated with depression.

Annotation G. Are There Other Co-Occurring Mental Health Illnesses?

Other Co-Morbid Psychiatric Conditions

Action Statement

Determine whether other psychiatric conditions are present and may complicate treatment.

Recommendations

  1. Patients presenting to primary care with evidence or suspicion of co-occurring psychiatric disorders should be offered referral to mental health specialty for evaluation and treatment. Conditions that should prompt the primary care provider to consider referral include:
    • Extreme weight loss suggestive of anorexia nervosa
    • Extensive history of childhood abuse, unstable or broken relationships, or criminal behavior starting before or during adolescence, that is suggestive of a personality disorder
    • A pattern of "binging" (rapid and excessive consumption of food) and/or "purging" (use of self-induced vomiting, laxatives, or diuretics) to control weight that may suggest bulimia nervosa
    • Frequent and disabling nightmares or flashbacks suggestive of post traumatic stress disorder
    • Other major mental disorders (e.g., schizophrenia or bipolar disorder) likely to significantly complicate the primary care management of depression symptoms
  1. Patient presenting with unexplained physical symptoms and depression should be offered referral to a mental health specialist as these may represent a somatoform disorder.

Assessment for Bipolar Disorder

Action Statement

Determine if the patient has bipolar disorder.

Recommendations

  1. The possible existence of bipolar disorder should be assessed in patients presenting with depressive symptoms, using a clinical interview or a bipolar questionnaire.
  2. Patients suspected to have bipolar disorder should be referred to mental health for diagnosis and management.

For further information on assessment and screening tools for Bipolar Disorder see: http://www.cqaimh.org/stable.html External Web Site Policy, and VA/DoD Clinical Practice Guideline for Bipolar Disorder External Web Site Policy.

Substance Use Disorder (SUD)

Action Statement

Identify patients who require evaluation and treatment for substance use disorder.

Recommendations

  1. Patients should be asked about any current or recent use of caffeine, nicotine, alcohol, or other psychoactive substances. [I]
  2. Patients with current alcohol or other drug dependence should be managed according to the VA/DoD Guideline for Substance Use Disorder. [I]

Unexplained Symptoms

Action Statement

Determine if the patient has other somatoform disorders.

Recommendations

  1. Patients presenting with unexplained physical symptoms and depression should be offered referral to a mental health specialist as these may represent a somatoform disorder.
  2. When referring a patient with possible MDD and unexplained physical symptoms to a mental health specialist, the primary care provider needs to:
    • Build a trust relationship with the patient
    • Carefully explain the reason for referral before and after it is recommended
    • Set a follow-up appointment for after the referral

Annotation H. Are There Symptoms of Depression or Functional Impairment That Do Not Meet DSM IV-TR Criteria For MDD?

  1. Depression Not Otherwise Specified

    Action Statement

    Identify patients with a diagnosis of depression not otherwise specified (NOS) and treat accordingly.

    Recommendations

    1. Patients with depressive symptoms who do not meet the diagnostic criteria of MDD (less than 5 symptoms and duration of less than two weeks) should be diagnosed with depression not otherwise specified (NOS).
    2. If the diagnosis of depression NOS is made, the primary care provider may consider an initial approach of "watchful waiting" or a 4 to 8 week trial of support, psychoeducation, self-help, and exercise.
  1. Dysthymia

    Action Statement

    Identify patients with a diagnosis of dysthymia and treat accordingly.

    Recommendations

    1. The diagnosis of dysthymia may be considered in patients who experienced a two-year period during which, for most days, the individual experiences depressed mood for more than half of the day, along with at least two of the following symptoms:
      • Increased or decreased appetite
      • Insomnia or hypersomnia
      • Fatigue or low energy
      • Poor self-image
      • Reduced concentration or indecisiveness
      • Hopelessness
    1. Patients who initially experienced a depressive episode and continue to experience subsyndromal symptoms following recovery should be diagnosed as MDD in partial remission, even if those symptoms last more than two years.
    2. Primary care providers may consider antidepressant pharmacotherapy or a combined course of pharmacotherapy and psychotherapy if the patient is diagnosed with dysthymia, though the evidence suggests that the benefits of psychotherapy, and possibly pharmacotherapy, are lower than those found in treatment of major depression.
    3. In treating an elderly patient with dysthymia, psychotherapy should be considered, as some evidence suggests this is more effective than pharmacotherapy in this age group.

Annotation I. Provide Psychoeducation for Self-Management

(See Section 11 below)

Annotation J. Determine Level of Symptoms Severity of MDD and Functional Impairment

  1. Severity Classification and MDD Symptoms

    Action Statement

    Use evaluation of PHQ-9 scores and functional impairment to determine the level of severity of MDD symptoms for a patient with MDD.

    Recommendations

    1. The level of symptoms severity of MDD should be determined for the patient with diagnosed MDD based on the patient's symptoms score (PHQ-9) and level of functional impairment ascertained in the clinical psychiatric interview.
    2. The classification of mild, moderate, or severe MDD should be used to establish a baseline and track progress as treatment is initiated (see Table 6 in the original guideline).
    3. Key symptoms that may have impact on a patient's functional impairment should be considered when using this classification and may indicate assigning a higher level of severity than is determined by the PHQ-9 score.

Annotation K. Discuss Treatment Options and Patient's Preferences; Arrive at Shared Decision Regarding Treatment Goals and Plan

  1. Shared Decision and Treatment Plan

    Action Statement

    Including the patient in decisions about their medical care may increase adherence to treatment.

    Recommendations

    1. Patients should receive information that is reasonable for them about their treatment options.
    2. Patients should be informed about the risks and benefits of each treatment option.
    3. Patients should be assessed for their understanding of the ramifications of their choice.

Annotation L. Is There Indication for Referral to Mental Health Specialty?

  1. Mental Health Referral/Consultation

    Action Statement

    Appropriately refer patients with MDD or related disorders to mental health professionals.

    Recommendations

    1. Patients with severe or complicated depressive disorder should be referred to mental health specialty care.
    2. Patients with depressive disorders may need more advanced specialized management if any of the following complicating factors that may influence treatment decisions exist:
      • Failure to respond to adequate depression treatment or otherwise complicating treatment
      • A co-existing mental health disorder that significantly complicates treatment (e.g., a history of hypomania or a manic episode, post traumatic stress disorder [PTSD], psychosis, substance use disorder)
      • A co-existing medical condition that significantly complicates the treatment planning for depression
      • Urgent or unstable psychiatric conditions
      • Personal or family history of suicide attempts or suicidal ideas necessitating psychiatric hospitalization
      • A past depressive episode involving severe loss of functioning or other life threatening consequences.
    1. The primary care provider should consider consultation with mental health specialists in the following circumstances:
      • Unclear diagnosis
      • Failure to respond to 2 or more antidepressants
      • Three months of treatment without desired clinical improvement
      • Need for, or patient request for, psychotherapy or combination of both medication and psychotherapy
      • Concerns about patient's adherence to treatment
      • Extreme levels of distress and/or extremely impaired functioning that, in the primary care provider's judgment, seem beyond the capabilities of the primary care setting.
    1. When weighing the need for consultation, the primary care provider should take into account the patient's preferences and common barriers to effective mental health consultation such as:
      • Patient reluctance to see a mental health care specialist
      • Feasibility for the patient
      • Geographical distance from consultants
      • Length of time to consultant availability

Annotation M. Initiate Treatment Strategies Effective for Depression

  1. Initial Treatment

    Psychoeducation and Self-Management

    Action Statement

    All patients, and when appropriate, family members, should be provided education regarding depression, its treatment options, and self-management strategies.

    Recommendations

    1. Psychoeducation should be provided for individuals with depression at all levels of severity and in all care settings and should be provided both verbally and with written educational materials. [I]
    2. There should be education on the nature of depression and its treatment options and should include the following: [I]
      • Depression is a medical illness, not a character defect
      • Education on the causes, symptoms, and natural history of major depression
      • Treatment is often effective and is the rule rather than the exception
      • The goal of treatment is complete remission; this may require several treatment trials
      • Treatment of depression can lead to decreased physical disability and longer life
      • Education about various treatment options, including the advantages and disadvantages of each, side effects, what to expect during treatment, and the length of treatment
    1. When antidepressant pharmacotherapy is used, the following key messages should be given to enhance adherence to medication: [B]
      • Side effects often precede therapeutic benefit, but typically recede over time while benefits increase
      • A slight increase in suicidal ideation in the first month may occur and patients should contact their provider if this does occur
      • Successful treatment often entails medication and/or dosage adjustments in order to maximize response while minimizing side effects
      • Most people need to be on medication for at least 6 to 12 months after adequate response
      • It usually takes 2 to 6 weeks before improvements are seen
      • Continue to take the medication even after feeling better
      • Do not discontinue taking medications without first discussing with your provider
    1. Education focused on treatment adherence should focus on the following: [I]
      • Education on the risk of relapse in general; essentially, that relapse risk is high, particularly as the frequency of prior episodes increases
      • Education on how to monitor symptoms and side effects
      • Education on early signs and symptoms of relapse or recurrence, along with encouragement to seek treatment early in the event these signs or symptoms occur
    1. A major goal for the use of self-management strategies is to enhance the patient's active engagement in treatment. A common strategy is for a patient to collaboratively select one or two self-management goals at a time to pursue during treatment. Education should incorporate principles of self-management and may include information and goals related to:
      • Nutrition – Often patients with MDD do not have a balanced diet. Expert opinion suggests that diet should be included in the therapeutic content. However, there is not a robust evidence base that improving diet impacts treatment outcomes. [I]
      • Exercise (see Section 23 below) – MDD is associated with low levels of exercise. There is fairly strong evidence that exercise often has significant antidepressant effects. [B]
      • Bibliotherapy (see Section 22 below on Guided Self-Help) – Bibliotherapy (the use of self-help texts) may be helpful to patients for understanding their illness and developing self management skills. Guided self-help programs which entail a cognitive behavioral focus and intermittent monitoring and oversight by a health care professional are significantly more effective than no treatment control and as effective as more traditionally delivered modes (e.g., individual or group cognitive behavioral therapy [CBT]). [B]
      • Sleep hygiene – Patients with MDD often have substantial sleep problems including insomnia, hypersomnia, and disturbances of sleep maintenance. Education regarding appropriate sleep hygiene should be included for patients exhibiting any sleep disturbances. [I]
      • Tobacco use – Tobacco use has been demonstrated to impact on the recovery of depression; therefore, patients being treated for depression should be advised to abstain until their symptoms remit. Referral or treatment of nicotine dependence should be considered in patients treated for depression. [I]
      • Caffeine use – Expert opinion suggests that excessive caffeine use may exacerbate some symptoms of depression such as sleep problems or anxiety symptoms. [I]
      • Alcohol use and abuse – Even low levels of alcohol use have been demonstrated to impact on the recovery of depression; therefore, patients being treated for depression should be advised to abstain until their symptoms remit. [I]
      • Pleasurable activities (see Section 21 below on Behavioral Activation) – Depression has been conceptualized by behavioral theorists as the loss or significant decrement of reinforcing activities. Behavioral activation (the systematic scheduling and monitoring of pleasurable or reinforcing activities) has been shown to have significant antidepressant effects. [B]
    1. Psychoeducational strategies should be incorporated into structured and organized treatment protocols, which entail structured systematic monitoring of treatment adherence and response and self-management strategies. [B]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Adherence to treatment should be directly and routinely assessed Katon et al., 2001; Lin et al, 2003; Vergouwen et al., 2003; Williams et al., 2007 I Good B
    2 Initial brief educational messages addressing medication adherence issues to enhance acute phase adherence Lin et al., 1995 I Good B
    3 In primary care settings, use of collaborative care or other structured protocol approaches enhances adherence Katon et al., 2001; Lin et al., 2003; Vergouwen et al., 2003; Williams et al., 2007 I Good B
    4 Patient education should focus on the nature and course of depression, treatment options, the importance of adherence, and relapse prevention strategies Institute for Clinical Systems Improvement (ICSI), 2006 III Fair C
    5 Exercise is an effective self-management strategy Babyak et al., 2000; Blumenthal et al., 1999; Carlson, 1991; Craft & Landers, 1998; Dunn et al., 2005; Harris, Cronkite, & Moos, 2006; Knubben et al., 2007; Lawlor & Hopker, 2001; Mather et al., 2002; North, McCullagh, & Tran, 1990; Trivedi et al., 2006 I Good B
    6 Guided self-help or bibliotherapy is an effective self-management strategy Cuijpers, 1997; National Collaborating Centre for Mental Health, 2004 I Good B
    7 Behavioral activation is an effective self-management strategy Dimidjian et al., 2006 I Good B

    QE, quality of evidence; SR, strength of recommendation

    Watchful Waiting

    Action Statement

    Careful prospective monitoring of symptoms to determine if they persist or abate is a supported strategy in patients with relatively few depressive symptoms, prior to initiation of medication or psychotherapy.

    Recommendations

    1. In patients with likely adjustment disorder, bereavement or subsyndromal depression rather than major depression, a period of watchful waiting (WW) should be initiated. WW should only be considered when systematic follow-up assessments can be conducted.
    2. Watchful waiting should incorporate psychoeducation, general support, and prospective symptom monitoring over a 4 to 8 week period.

    Monotherapy

    Action Statement

    The initial treatment strategy for patients diagnosed with MDD, mild or moderate, should start with either psychotherapy or a single antidepressant.

    Recommendations

    1. Patients who are diagnosed with mild-moderate MDD should receive an initial trial of monotherapy that incorporates either an antidepressant medication or psychotherapy (see Table 7 in the original guideline).
      • Patient preferences, resources, and tolerability of treatment should be considered in determining the choice between an antidepressant and psychotherapy.
      • Monotherapy should be optimized before proceeding to subsequent strategies by monitoring outcomes, maximizing dosage (medication or psychotherapy), and allowing sufficient response time (8-12 weeks).

    Combination Psychotherapy and Antidepressants

    Action Statement

    Combination treatment of antidepressant medication and psychotherapy should be used for moderate to severe MDD or as a potential strategy for managing patients who have had partial or non-response to monotherapy.

    Recommendations

    1. In patients with moderate to severe MDD, the initial treatment strategy should include both empirically validated psychotherapy and an antidepressant medication.
    2. Patient preferences, resources, and tolerability of treatment may override this recommendation in certain circumstances. In these circumstances, more aggressive monotherapy should be considered as well as adapting treatment when response is not robust.

    Treatment of Complex Patients

    Action Statement

    Certain antidepressants or combinations of psychotropic medications may be required in severe or refractory cases of MDD.

    Recommendations

    1. More complex treatment strategies should be limited to patients with a diagnosis of MDD who are refractory to the above treatment strategies or in complex cases such as patients with psychiatric comorbidity.
    2. The use of complex treatment strategies should be limited to those with expertise, such as a mental health provider.
    3. The use of complex strategies increases the burden to patients, the chance of adverse events, and costs. Therefore, structured monitoring and assessment is critical in the management of these patients.

    Somatic Treatment

    Action Statement

    Certain somatic therapies (e.g., electro-convulsive therapy [ECT], vagus nerve stimulation [VNS]) may be required in severe or refractory cases of MDD (i.e., during pregnancy, in catatonic patients, and in elderly patients diagnosed with psychotic depression).

    Recommendations

    1. Somatic treatment strategies should be prescribed and monitored only by physicians who have specific training and expertise in the management of treatment-resistant depression and the use of these devices.
      • ECT is a recommended treatment strategy for patients who have failed multiple other treatment strategies.
      • ECT may be a first line treatment for pregnant women, patients with psychotic depression, catatonic patients, or patients who have severe self-neglect issues.
      • Vagus nerve stimulation is currently U.S. Food and Drug Administration (FDA) approved only for treatment of resistant depression for patients who have failed to respond to at least 4 adequate medications and/or ECT trials.

    Inpatient and Residential Settings

    Action Statement

    Severely impaired patients with MDD may require acute or subacute stabilization.

    Recommendations

    1. Patients who express suicidal or homicidal thoughts or who are unable to provide basic self-care should be considered for admission to an inpatient psychiatric unit.
    2. Patients with unstable social networks or who lack significant support in the community may require subacute care in a residential setting.

Annotation N. Address Psychosocial Needs

Psychosocial Issues

Action Statement

Psychosocial rehabilitation services should be offered to individuals with MDD who have significant, unmet psychosocial needs.

Recommendations

  1. Individuals with MDD should be assessed for any significant, unmet psychosocial needs or situational stressors. These include, but are not limited to: [B]
    • Inadequate or no housing
    • Financial difficulties, especially if unable to meet basic needs
    • Problematic family relationships or situations (including caregiver burden or domestic violence)
    • Poor social support
    • Religious and spiritual problems
    • Occupational problems
    • Difficulties with activities of daily living or instrumental activities of daily living
    • Any other acute or chronic situational stressors
  1. If unmet psychosocial needs are identified, psychosocial rehabilitation services should be offered to individuals with MDD at all levels of severity, regardless of population or setting, and regardless of the type of pharmacotherapy or psychotherapy being administered. [B]
  2. Psychosocial rehabilitation services may include, but are not limited to, referrals to community social service agencies, emergency and transitional housing programs, vocational rehabilitation, agencies providing financial assistance, support groups, senior centers, and supervised living situations (e.g., foster homes, assisted living facilities). [C]

Evidence Table

  Evidence Source QE Overall Quality Benefit SR
1 Psychosocial stressors as etiological factors for MDD:
  • Environmental stressors are just as significant as genetics in the etiology of MDD
Tennant, 2002 II-2 Fair Moderate B
  • Life events, social support and marital relationships play a role in the onset of MDD
Paykel et al., 1996 II-2 Fair Moderate B
  • Major life stress is often an important factor in the first episode of MDD
  • Non-severe life events are capable of triggering a recurrence of depression
Monroe et al., 2006 I Good Moderate A
2 Barriers to adherence to treatment for MDD: Low-income minority women may have increased difficulty with adherence to treatment, antidepressant medications (ADM) or cognitive behavioral therapy (CBT) Miranda et al., 2006 I Fair Moderate C
3 Influencing treatment outcome:
Adverse life events and/or perceived poor social support influence the medium-term outcome of all psychiatric patients with MDD. Leskelä et al., 2006 II-2 Fair Moderate B
Psychosocial factors appear to play a role in the outcome of mild depressions; however, they are unimportant in the subsequent course of severe and recurrent depressions. Paykel et al., 1996 II-2 Fair Moderate B
4 Psychosocial rehabilitation services may lessen vulnerability to MDD, resulting in improved treatment adherence and improved outcomes. Working Group Consensus III Poor N/A I

MDD, major depressive disorder; QE, quality of evidence; SR, strength of recommendation

Annotation O. Complete Assessment of Treatment Response; Review Current Medication; Assess for Dangerousness

  1. Treatment Response

    Assess Depressive Symptoms, Functional Status and Suicide Risk

    Action Statement

    Assess depressive symptoms, functional status, and suicide risk to determine treatment effects.

    Recommendations

    1. The PHQ-9 should be used to monitor treatment response at 4 to 6 weeks after initiation of treatment, after each change in treatment, and periodically until full remission is achieved. [B]
    2. In patients who reach full remission, assessment of symptoms should be continued periodically to monitor for relapse or recurrence. [B]
    3. Patients with suicidal ideation should have a careful evaluation of suicide risk. [A]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Systematic assessment of treatment response is a component of efficacious primary care treatment models Bower et al., 2006; Gilbody et al., 2006; Williams et al., 2007 I Good A

    QE, quality of evidence; SR, strength of recommendation

    Tolerability of Treatment

    Action Statement

    Assess for adverse effects and tolerability after any change of treatment strategy.

    Recommendations

    1. Using a clinical interview, assess for treatment burden (e.g., medication side effects or adverse effects, attending appointments) after initiating or changing treatment, when the patient is non-adherent to treatment, or when the patient is not responding to treatment.
    2. Identified side effects should be managed to minimize or alleviate the side effects.

    (See Appendix D-2: 'Antidepressant Adverse Drug Effects: Receptor Affinities and Relative Comparisons' in the original guideline).

    Adherence to Treatment

    Action Statement

    Systematically assess adherence to treatment with all depressed patients. Employ educational and systems interventions to enhance adherence for patients at high risk of poor adherence. Consider evidence-based psychotherapy in combination with antidepressant medications.

    Recommendations

    1. Adherence should be assessed directly and routinely, targeting common reasons for nonadherence (e.g., side effects, lack of efficacy, feeling better). [B]
    2. Providers should give simple educational messages regarding antidepressant use (e.g., take daily, understand gradual nature of benefits, continue even when feeling better, do not stop without checking with the provider, and specific instructions on how to address issues or concerns) in order to increase adherence to treatment in the acute phase of treatment. [B]
    3. In primary care, utilize collaborative care personnel (e.g., nurses, social workers, psychologists) and systems strategies to enhance adherence to treatment beyond the acute phase. Collaborative care strategies used by mental health specialists focus on patient education via systematic in-person or telephonic follow-up/monitoring to address adherence, relapse prevention issues and self-management strategies. [B]
    4. For patients who are at high risk for non-adherence to antidepressant medication, refer for psychotherapy to increase medication adherence and decrease the chance of treatment discontinuation. [B]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Assess adherence to treatment directly and routinely Katon et al., 2001; Lin et al., 2003; Vergouwen et al., 2003; Williams et al., 2007 I Good B
    2 Brief educational messages at the beginning of treatment, given by providers, addressing medication adherence issues enhance acute phase adherence Lin et al., 1995 I Good B
    3 In primary care settings, utilize collaborative care approaches to enhance adherence. These approaches should use education and systematic monitoring, specifically addressing adherence and self-management strategies Katon et al., 2001; Lin et al., 2003; Vergouwen et al., 2003; Williams et al., 2007 I Good B
    4 For patients who are willing, refer patients taking antidepressant medication to psychotherapy to increase adherence and decrease treatment discontinuation de Jonghe et al., 2001; Pampallona et al., 2004 I Good B

    QE, quality of evidence; SR, strength of recommendation

    Re-Evaluate Diagnoses and Treatment Strategy for Non-Response

    Action Statement

    In patients who do not respond to an adequate treatment trial, reconfirm the diagnoses and assess for concurrent problems that may adversely affect treatment.

    Recommendations

    1. In treatment of non-responders, the diagnosis of MDD should be reconfirmed and the patient should be assessed for factors that may contribute to non-response. Referral to mental health specialty for a comprehensive assessment may be considered. Evaluation should include:
      • Assessment for existence of psychiatric conditions that may present initially with depressive symptoms or adversely affect treatment response, including bipolar disorder, substance abuse, post traumatic stress disorder, generalized anxiety or panic disorder and in older adults, dementia.
      • Assessment for medical conditions that may present with depressive symptoms. This may require additional history, physical examination, and laboratory testing. Poorly controlled medical conditions (e.g., chronic pain, congestive heart failure [CHF]) that may potentiate depression should be treated aggressively.
      • Assessment for psychosocial problems that may contribute to treatment nonresponse. Domains assessed may include financial, legal, relationship, work, or negative life events.

Annotation P. Is the Patient's Condition Improving and Is the Current Treatment Strategy Tolerable?

  1. Symptom Improvement

    Action Statement

    Determine if depressive symptoms are significantly improved, defined as a:

    • Five-point reduction OR score <10 on the PHQ-9
    • Twenty-five percent or greater reduction in score on an accepted standardized instrument.

    Recommendations

    1. If the patient has shown clinically significant improvement in depressive symptoms, but is not yet at remission, and if medication has been well tolerated, then continuing to prescribe and raising the dose is recommended.
    2. Improvement with psychotherapy is often slower than with pharmacotherapy. A decision regarding progress with psychotherapy and the need to change or augment this type of treatment may require 8 to 10 weeks before evaluation.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Five-point reduction OR score <10 on the PHQ-9 indicates improvement in MDD symptoms Kroenke, Spitzer, & Williams, 2001 I Good A

    MDD, major depressive disorder; PHQ, patient health questionnaire; QE, quality of evidence; SR, strength of recommendation

Annotation Q. Continue Current Treatment Strategy; Reassess By 4-6 Weeks

  1. Continue Current Treatment Strategy/Reassess by 4-6 Weeks

    Action Item

    Ensure patient remains on treatment with desired outcome.

    Recommendation

    1. After initiation of therapy or change in medication or dose adjustment, patients should be monitored in person or by phone on a monthly basis. Clinicians can use these encounters to assess adherence to medication and psychotherapy, emergence of adverse effects, symptom breakthrough, suicidality, and psychosocial stress.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Four to six week reassessment for treatment response Schulberg et al., 1998; Shelton, 1999 I Fair B
    2 Rate of response for individuals with MDD who show no improvement by week four is low and no better than placebo; change treatment regimen Quitkin et al., 1996 I Good A
    3 Nonresponse to fluoxetine should not be declared until 8 weeks of treatment have elapsed Quitkin et al., 2003 I Good A

    MDD, major depressive disorder; QE, quality of evidence; SR, strength of recommendation

Annotation R. Full Remission?

  1. Full Remission

    Action Statement

    The goal of antidepressant therapy should be the lowest possible degree of depressive symptomatology in order to minimize risk of later relapse.

    Recommendations

    1. Full remission in defined as:
      • PHQ-9 score of 4 or less, maintained for at least 1 month, OR
      • Beck Depression Inventory (BDI) score of 10 or less, maintained for at least 1 month, OR
      • Hamilton Rating Scale for Depression (HRSD) of 7 or less, maintained for at least 1 month

    Upon complete remission of depressive symptoms, patients who receive continuation phase treatment of antidepressants (lasting at least 6 months) are less likely to suffer a relapse. Patients at high risk for recurrence are less likely to recur if treatment is continued beyond the continuation phase.

Annotation S. Continue Treatment to Prevent Relapse

  1. Continuation Treatment

    Action Statement

    Continue antidepressant treatment for at least six months to decrease the risk of relapse after initial remission is achieved.

    Recommendations

    1. In patients with MDD who achieve remission with antidepressant medication, treatment should be continued at the same dose for an additional 6 to 12 months to decrease the risk of relapse. [A]
    2. In patients who achieve remission with psychotherapy, continuation phase psychotherapy should be considered for patients at higher risk for relapse, taking into account personal history, family history, and severity of current illness.
    3. Cognitive behavioral therapy (CBT), cognitive therapy (CT), or mindfulness-based cognitive therapy (MBCT) should be used during the continuation phase of treatment with patients at high risk for relapse (i.e., two or more prior episodes, double depression, unstable remission status) to reduce the risk of subsequent relapse/recurrence. This can occur after pharmacotherapy has ended or as a combined intervention for patients continuing pharmacotherapy. [A]
    4. Depressive symptoms and functional status should be assessed periodically, more frequently early in the continuation phase, as this corresponds to the highest risk period for relapse. [C]
    5. A relapse prevention plan should be developed that addresses duration of treatment, prognosis, self-management goals, and self-monitoring. [B]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 The median six-month risk of relapse is 40% (range 11% to 52%) Gartlehner et al., 2007; Geddes et al., 2003; Limosin et al., 2004; Oldehinkel, Ormel, & Neeleman, 2000 I Good A
    2 Continuation phase antidepressant treatment decreases relapse by 70% Gartlehner et al., 2007; Geddes et al., 2003 I Good A

    QE, quality of evidence; SR, strength of recommendation

Annotation T. Continue Maintenance Therapy in Primary Care

  1. Maintenance Treatment to Prevent Recurrence

    Action Statement

    Continue antidepressant treatment in patients who recover from depression but are at high risk for recurrence.

    Recommendations

    1. Patients should be assessed for risk of recurrence after completing the continuation phase treatment. [I]
    2. Indications for maintenance:
      • Two or more prior episodes [B], chronic major (> 1 year), or double depression
      • A family history of bipolar disorder and more severe depression as defined by: the need for hospitalization, strong suicidal ideation or behaviors, longer duration of symptoms, and more residual symptoms after response to treatment [C]
      • Co-morbid substance abuse/dependence, anxiety disorders [C]
      • Ongoing psychosocial stressors: low socioeconomic status, acrimonious relationship, chronic/severe medical illness [C].
    1. Maintenance treatment should be continued at the same dosage that was used during the continuation phase, and continued for at least 12 months and possibly indefinitely. [A]
    2. Consider maintenance phase psychotherapy for a very select population. [B]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Continued antidepressants have been demonstrated to be effective in reducing risk of relapse/recurrence Gartlehner et al., 2007; Geddes et al., 2003 I Good A
    2 Continuation phase CBT, CT, or MBCT reduces the risk of relapse/recurrence with recurrently depressed patients who have or have not discontinued medication and who are at higher risk of relapse (i.e., 3 or more prior episodes, earlier onset, unstable remission) Bockting et al., 2005; Jarrett et al., 2001; Ma & Teasdale, 2004; Teasdale et al., 2000 I Good A
    3 Relapse/recurrence prevention effects appear to be fairly durable Fava et al., 2004; Paykel et al. 2005 I Good A
    4 A variety of dysfunctional cognitive variables, which are typically targets of CT and respond favorably to CT, significantly predict relapse/recurrence Alloy et al., 2006; Beevers et al., 2003; Iacoviello et al., 2006; Mongrain & Blackburn, 2005; Petersen et al., 2004; Segal et al., 2006; Teasdale et al., 2001; Teasdale et al., 2002 III Fair C

    CBT, cognitive behavioral therapy; CT, cognitive therapy; MBCT, mindfulness-based cognitive therapy; QE, quality of evidence; SR, strength of recommendation

Annotation U. Adjust/Modify Treatment

  1. Adjust/Modify Treatment for Partial or No Response

    Action Statement

    The selection of an antidepressant for a patient with MDD should be based on safety, comorbid conditions, symptoms, concurrent medication, and previous antidepressant response.

    Recommendations

    1. The choice of antidepressant should be based on safety, the patient’s co-morbid conditions, symptoms, concurrent medication, and previous response: [I]
      • Antidepressants in dosage forms that are taken once or twice a day should be prescribed to enhance patient adherence
      • Antidepressant doses should be increased based on patient tolerance and response
      • An adequate trial to response of an antidepressant is a therapeutic dose for 4 to 6 weeks

    Onset Response

    1. Patients who do not tolerate an initial antidepressant prior to responding should be switched to a different first-line antidepressant.
    2. Patients who demonstrate a 25 percent improvement or greater, without achieving remission, from their baseline PHQ-9 score after 6 weeks of treatment have the following options:
      • Continue present management and reassess in 4-6 weeks
      • Consider raising the dose in patients who tolerate to accelerate remission
    1. Patients who do not achieve a 25 percent improvement from their baseline PHQ-9 after 6 weeks of medication have the following options:
      • Consider raising the dose in patients who tolerate to accelerate remission
      • Switch to a different first line antidepressant and repeat the process starting at Box 32 of the clinical algorithm (see the original guideline)

    Treatment Response-Remission

    1. Patients who do not achieve remission (a PHQ-9 score < 5) after 8 to 12 weeks with an initial antidepressant have the following options:
      • Increase in the dose, provided the dose has not already been maximized and is tolerable
      • Current medication could be augmented with another medication (see #8 above) or combined with psychotherapy
      • Switch to a different first line antidepressant and repeat the process starting at Box 32 of the clinical algorithm (see the original guideline)
    1. Patients who do not achieve remission after 8 to 12 weeks of a second treatment trial using a first-line antidepressant have the following options available:
      • Current medication could be augmented with another medication (see #8 above) or combined with psychotherapy (if not already tried)
      • Consider modifying therapy and restarting the course of therapy with a different drug, following the steps and options discussed above starting at Box 32
      • Consider a referral to mental health services
    1. Patients who do not achieve remission after adequate trials of two first-line antidepressants should either be switched to a new antidepressant from a different class (consider venlafaxine if not already tried) or receive augmentation with either medications or psychotherapy.
    2. Patients who do not achieve remission after adequate trials of three different antidepressants should either receive augmentation with either medications or psychotherapy or receive combination antidepressant treatment or electro-convulsive therapy (ECT).
  1. Care Management

    Action Statement

    Care management should be considered for patients with MDD who are treated in primary care settings.

    Recommendations

    1. Consider 6 to 12 months of care management for patients with mild to moderate major depression. [B]
    2. Care management components may be delivered by telephone, should be delivered by individuals with the relevant training and skill set, and should include: [B]
      • Depression symptom monitoring using a validated instrument (e.g., PHQ-9) at each contact
      • Depression education (illness, course, treatments, timing of expected treatment response, active coping strategies such as exercise and leisure planning)
      • Antidepressant medication monitoring to include tolerability and adherence
      • Initiation of crisis assessment and intervention as needed
      • Care coordination with primary care and mental health clinicians as needed
    1. Care managers should:
      • Encourage and support regular attendance for scheduled visits with medical or mental health care providers and adherence to psychotherapies or antidepressant therapies as appropriate
      • Look for possible manic or hypomanic episodes or alcohol/substances abuse to facilitate referral to mental health
      • Participate in routine clinical review of the care manager caseload and facilitate feedback of mental health specialist recommendations

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Compared to usual primary care, care management improves depression outcomes for patients with mild to moderate MDD Bower et al., 2006; Gilbody et al., 2006; Williams et al., 2007 I Good A
    2 Care management appears more effective when continued for at least six months Williams et al., 2007 II Fair B
    3 Care management is effective when delivered by telephone Gilbody et al., 2006; Williams et al., 2007 I Good A
    4 Essential elements of care management are: prospective follow-up to include symptom monitoring and treatment adherence, patient education, and coordination of primary care and mental health services Gilbody et al., 2006; Williams et al., 2007 II Fair B
    5 In efficacious studies, care management functions routinely included general support Gilbody et al., 2006; Williams et al., 2007 I Fair B
    6 In almost all studies, care managers participated in case reviews with a mental health professional who typically was a psychiatrist Williams et al., 2007 I Good A

    MDD, major depressive disorder; QE, quality of evidence; R, final grade of recommendation

  1. Pharmacologic Treatment

    General

    Recommendations

    1. There is insufficient evidence to recommend one antidepressant medication over another for all patients.
      • The choice of medication is based on side effect profiles (see Appendix D-2 in the original guideline), history of prior response, family history of response, type of depression, concurrent medical illnesses, concurrently prescribed medications, and cost of medication
      • Generally, selective serotonin reuptake inhibitors (SSRIs) or venlafaxine are first line antidepressants for patients in the primary care setting because of their low toxicity and ease of administration relative to other antidepressants
      • Generally, initial doses used for the elderly should be lower than in healthy adults
      • Prior to discontinuing an antidepressant as a failure, providers should ensure that an appropriate dose titration and target dose range has been achieved and an adequate response period allowed (a minimum of four to six weeks)
      • Discontinuation of antidepressant maintenance therapy should be done with a slow taper, as it may result in adverse withdrawal symptoms or return of original depressive symptoms. Tapering should be guided by the elimination half-life of the parent compound and metabolites, and by close monitoring of depressive symptoms (see Appendix D-3 in the original guideline).

    Selective Serotonin Reuptake Inhibitors

    Action Statement

    SSRIs along with the serotonin norepinephrine reuptake inhibitors (SNRIs), such as bupropion and mirtazapine, are considered a first-line treatment option for adults with MDD.

    Recommendations

    1. All of the SSRIs, excluding fluvoxamine, may be used as first-line agents in the treatment of adults with MDD.
    2. Patients who do not remit or are intolerant of one SSRI may be switched to another SSRI or to another class of antidepressant.
    3. Patients who do not remit or are intolerant to two or more SSRIs should be switched to a different class of antidepressant.
    4. Maximizing the dose of an SSRI should be considered for patients who show no response or partial response.
    5. Augmentation may be considered for those who show only partial response to an SSRI.
    6. When SSRIs are prescribed, the following should be considered:
      • The potential for pharmacokinetic and pharmacodynamic drug interactions
      • The potential for discontinuation symptoms particularly for the shorter-half life SSRIs
      • Drug specific side effects in selecting specific SSRI for patients who may be sensitive to these effects (see Appendix D-2 in the original guideline).
    1. Avoid paroxetine in pregnant women.
    2. When using SSRIs in pregnant women, the potential for increased risk of persistent pulmonary hypertension of the newborn should be considered.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 No evidence of increased efficacy by dose escalation within first 4 weeks. Dose escalation after 6 weeks appeared less effective than continuing same dose. Limited efficacy for dose escalation after 8 weeks Ruhe et al., "Dose escalation," 2006 I Poor I
    2 SSRIs used in the later half of pregnancy increase the risk of persistent pulmonary hypertension compared to non-SSRI antidepressants Chambers et al., 2006 II Fair B
    3 All SSRIs are equally effective for initial treatment of major depression Hansen et al., 2005 I Good A
    4 Sertraline has higher rates of diarrhea than citalopram, fluoxetine, fluvoxamine, and paroxetine Gartlehner et al., 2007 I Fair B
    5 Of the SSRIs, paroxetine has the highest reported rate of discontinuation syndrome and fluoxetine the lowest. Gartlehner et al., 2007 I Fair B
    6 Among the SSRIs, paroxetine has the highest rate of sexual dysfunction and weight gain. Gartlehner et al., 2007 I Fair B
    7 After failure on one SSRI, patients may still respond to another SSRI Ruhe et al., "Switching antidepressants, " 2006; Rush et al., "Bupropion-SR," 2006 I Good A
    8 Fluoxetine is equal in efficacy to imipramine for atypical depression, although more tolerable McGrath et al., 2006 I Good A
    9 In an analysis of epidemiological databases in various developed countries, SSRIs are associated with lower suicide rates Gibbons et al., 2005; Korkeila et al., 2007; Tiihonen et al., 2006 II Fair B
    10 Initiation of SSRIs may increase suicidal ideation or behaviors Tiihonen et al., 2006 II Fair B

    QE, quality of evidence; SR, strength of recommendation; SSRIs, selective serotonin reuptake inhibitors.

    Serotonin Norepinephrine Reuptake Inhibitors (SNRIS)

    Action Statement

    SNRIs, along with the SSRIs, bupropion, and mirtazapine, are considered a first line treatment option for adults with MDD.

    Recommendations

    1. SNRIs may be used as first line agents in the treatment of adults with MDD.
    2. Patients who do not remit or are intolerant of an SNRI may be switched to another class of antidepressants.
    3. SNRIs may be considered as a treatment option in patients who have not remitted to treatment with one or more second generation antidepressants (SSRIs, bupropion, or mirtazapine).
    4. SNRIs should be initiated at a low dose to improve tolerability and then increased to an effective dose.
    5. Maximizing the dose of venlafaxine may be considered for patients who show no response or a partial response to antidepressant treatment.
    6. Augmentation may be considered for patients who show no response or a partial response to antidepressant treatment.
    7. Consider the potential for drug interactions with this class.
    8. Consider the potential for discontinuation symptoms with this class.
    9. Avoid duloxetine in patients with substantial alcohol use or evidence of chronic liver disease.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 SNRIs have been shown to be superior to placebo for the treatment of adults with MDD Gartlehner et al., 2007 I Good A
    2 Response and remission rates with venlafaxine may be slightly higher than with the SSRIs, although this is balanced by higher rates of nausea and vomiting and discontinuation due to adverse effects Gartlehner et al., 2007; Hansen et al., 2005; Smith et al., 2002 I Good C
    3 Although one meta-analysis reported a significantly greater treatment effect with venlafaxine than with duloxetine, another meta-analysis and pooled results of two similar double-blind RCTs report no statistically significant differences in treatment effect between the two SNRIs. Eckert & Lancon, 2006; Vis, van Baardewijk, & Einarson, 2005 I Good C
    4 SNRIs are effective in treating adult patients with MDD who have not responded to one or more trials with other second generation antidepressants (SSRIs, bupropion, or mirtazapine) Ruhe et al., "Switching antidepressants," 2006; Rush et al., "Acute and longer-term," 2006; Baldomero et al., 2005; Poirier & Boyer, 1999 I Good A

    QE, quality of evidence; SNRIs, serotonin norepinephrine reuptake inhibitors; SR, strength of recommendation; SSRIs, selective serotonin reuptake inhibitors.

    Bupropion

    Action Statement

    Bupropion, along with the SSRIs, SNRIs and mirtazapine, is considered a first-line treatment option for MDD.

    Recommendation

    1. Bupropion is a treatment option for patients with MDD for whom a first-line antidepressant is appropriate.
    2. Bupropion is an augmentation option for patients who have partially responded to a different antidepressant but have not achieved remission.
    3. Patients should be titrated to the dose of bupropion that is effective and tolerable without exceeding the maximum recommended daily dose. (See Appendix D-1 in the original guideline)
    4. Bupropion should be considered as an alternative antidepressant for patients who have experienced intolerable sexual side effects with other antidepressants.
    5. Bupropion may be considered for patients for whom weight gain would be problematic or for patients who experienced intolerable weight gain with another antidepressant.
    6. Bupropion may be considered for patients with MDD who desire to stop smoking.
    7. Bupropion should not be prescribed to patients with a history of seizure disorder or anorexia nervosa or bulimia.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Bupropion's response and remission rates are comparable to other first-line antidepressants Gartlehner et al., 2007; Hansen et al, 2005 I Good A
    2 Bupropion is a switching option for patients who have not responded or remitted to other first-line antidepressants Ruhe et al., "Switching antidepressants," 2006; Rush et al., "Buproprion-SR," 2006 I Good A
    3 Bupropion can be used to augment existing antidepressant treatment Trivedi et al., 2006 I Fair B
    4 Bupropion has a lower incidence of sexual side effects than the SSRIs Gartlehner et al., 2007 I Fair B

    QE, quality of evidence; SR, strength of recommendation; SSRIs, selective serotonin reuptake inhibitors.

    Mirtazapine

    Action Statement

    Mirtazapine, along with the selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and bupropion, is considered a first-line treatment option for MDD. Mirtazapine can also be used in combination with other antidepressants.

    Recommendations

    1. Mirtazapine is a treatment option for patients with MDD for whom a first-line antidepressant is appropriate.
    2. Mirtazapine in combination with another antidepressant is a treatment option for patients who have not achieved remission after several trials with a first-line antidepressant.
    3. Mirtazapine's dose should be titrated to a dose that is effective and tolerated without exceeding the maximum recommended daily dose. (See Appendix D-1 in the original guideline)
    4. Mirtazapine is a treatment option for patients who have experienced intolerable sexual side effects with other antidepressants.
    5. Mirtazapine should be avoided in patients for whom weight gain would be problematic.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Mirtazapine's response and remission rates are comparable to other first-line antidepressants Gartlehner et al., 2007 I Good A
    2 Mirtazapine is a switching option for patients who have not responded or remitted to other first-line antidepressants Ruhe et al., "Switching antidepressants," 2006 I Good A
    3 Mirtazapine can be used in combination with existing antidepressant treatment McGrath et al., 2006 I Good A
    4 Mirtazapine has a lower incidence of sexual side effects than the SSRIs Gartlehner et al., 2007 I Good A
    5 Mirtazapine is associated with weight gain more often than other first-line antidepressants Gartlehner et al., 2007 I Good A

    QE, quality of evidence; SR, strength of recommendation

    Tricyclic & Tetracyclic Antidepressants (TCAs)

    Recommendations

    1. TCAs may be considered agents for certain patients who do not respond to two or more trials with first line antidepressants or who have previously achieved remission with TCA. [B]
    2. TCAs should be used cautiously in the elderly. If the use of TCAs is necessary, nortriptyline and desipramine should be considered first. Due to increased side effects (e.g., central nervous system [CNS], anticholinergic, cardiovascular effects) associated with amitriptyline, imipramine and doxepin, the primary care physician should avoid the use of these agents in elderly patients.
    3. TCAs should be used cautiously in patients who are at high risk for suicide.
    4. Therapeutic response and dosing with a TCA may vary among patients due to both pharmacokinetic (e.g., enzyme induction by smoking), and pharmacodynamic (e.g., increased sensitivity in the elderly) differences.
    5. Therapeutic plasma concentrations should be monitored. Of the various TCAs, plasma concentration for desipramine, imipramine, and nortriptyline are best established. Although amitriptyline has been extensively studied, no clear relationship between response and plasma level has emerged. The use of therapeutic blood concentration can be of value in particular clinical instances, such as in patients who do not respond to or comply with therapy, patients on combination therapy, elderly patients, or patients with suspected drug toxicity.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Remission when treated with nortriptyline, for patient who failed two trials of first line antidepressants Rush et al., "Acute and longer-term," 2006 I Fair B
    2 Low-dose as well as high-dose TCAs are effective compared to placebo, with higher rates of withdrawal caused by side effects compared to first line antidepressants Arroll et al., 2005; Mottram, Wilson, & Strobl, 2006 I Fair B

    QE, quality of evidence; SR, strength of recommendation; TCA, tricyclic & tetracyclic antidepressants.

    Monoamine Oxidase Inhibitors (MAOIs)

    Action Statement

    MAOIs are considered a treatment option for adults with MDD who have not achieved remission after trials with other antidepressants such as SSRIs and SNRIs.

    Recommendations

    1. MAOIs may be considered a treatment option for adults with MDD who have not achieved remission on other antidepressants.
    2. Patient education must include dietary and drug restrictions, including the requirement for a tyramine-restricted diet with all monoamine oxidase inhibitors (with the exception of the lowest strength of the selegiline transdermal patch) to avoid a hypertensive crisis.
    3. Avoid concurrent use with other medications with serotonergic effects (e.g., other antidepressants, triptans, meperidine, tramadol, propoxyphene, dextromethorphan) due to the risk of serotonin syndrome.
    4. Avoid concurrent use with stimulants, vasoconstrictors and other medications with adrenergic effects due to the potential for hypertensive crisis.
    5. Allow adequate wash-out periods following treatment with other antidepressants or other drugs that interact with MAOIs based on half-life (e.g., 5 weeks after stopping fluoxetine therapy before starting an MAOI).

    Augmentation

    Action Statement

    Augmentation with medication may be considered for patients who have had a partial response to antidepressant monotherapy at a therapeutic dose after at least 6 weeks. The augmenting medication selected should be based on the patient's current medications (including antidepressants), co-morbid conditions, and adverse effect profile.

    Recommendations

    1. Augmentation can be introduced at any point in therapy, provided the patient has demonstrated a partial response to an existing antidepressant.
    2. Bupropion SR and anxiolytic buspirone are the preferred initial augmentation strategies given their ease of use and lower risk of toxicity.
    3. The atypical antipsychotics, with the exception of clozapine, can be considered as an alternative augmentation strategy, but should only be considered when other more established augmentation agents have either failed to result in remission or are contraindicated.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Augmentation can be introduced at any time during treatment, provided the patient has demonstrated a partial response to an existing antidepressant. Rush et al., "Acute and Longer-Term," 2006; Barbee, Conrad, & Jamhour, 2004 I Fair B
    2 Consider atypical antipsychotics after other augmenting agents have failed or are contraindicated Papakostas et al., 2007 I Fair B

    QE, quality of evidence; SR, strength of recommendation

    Psychostimulants

    Action Statement

    The psychostimulants including the amphetamines are not appropriate as monotherapy for the treatment of MDD. Psychostimulants may have a role as augmentation agents or in the treatment of other forms of depression such as in the medically-ill elderly or poststroke patients.

    Recommendations

    1. The psychostimulants may have a role as augmentation agents, although the evidence is stronger in support of other augmentation agents.
    2. The psychostimulants may be useful as monotherapy for patients who are demoralized, apathetic or physically inactive; specific patient populations are the medically ill elderly or post-stroke patients.
    3. Methylphenidate is the most studied and preferred psychostimulant.
    4. Only the immediate-release formulations of psychostimulants should be prescribed.
    5. Patients receiving psychostimulants should have their heart rate and blood pressure monitored. Psychostimulants should not be prescribed for patients with uncontrolled hypertension or cardiovascular disease.
    6. Psychostimulants are best avoided in patients with a co-morbid anxiety or for those in whom anxiety is a significant symptom of their depression.

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Stimulant drugs do not appear to be as effective as the conventional antidepressants in primary depression Satel & Nelson, 1989 I Fair B
    2 Stimulants in apathetic or depressed geriatric patients are likely to produce positive results, but outcomes frequently consisted of partial improvement Satel & Nelson, 1989 II Poor C
    3 Stimulants may be of value in refractory cases or in special cases, such as medically ill patients Satel & Nelson, 1989; Emptage & Semla, 1996 II Poor C

    QE, quality of evidence; SR, strength of recommendation

  1. Psychotherapy

    General Approach

    Action Statement

    Evidence-based short-term psychotherapies (cognitive behavioral therapy [CBT], interpersonal psychotherapy [IPT], and problem-solving therapy [PST]) are recommended treatment options for major depression. Other psychotherapies are treatment options for specific populations or are based on patient preference.

    Recommendations

    1. First-line psychotherapies (CBT, IPT, and PST) are recommended for the treatment of uncomplicated major depression: [A]
      • PST is recommended for psychotherapy provided in a primary care setting [A]
      • Treatments should be delivered by providers trained in the specific technique [B]
      • For severe depression (Hamilton rating scale for depression [HRSD] ≥20 or equivalent):
        • Behavioral Activation (BA) is a recommended treatment [B]
        • CBT is a treatment option [B]
    1. The recommended courses for first line psychotherapies (CBT, IPT, PST) are:
      • CBT and IPT: 16 to 20 sessions over approximately 16 weeks [A]
      • PST: six sessions over 3 months [A]
    1. In patients with a history of suicide attempts, CBT is a recommended treatment for reducing risk of suicide attempts. [B]
    2. For patients with severe, recurrent or chronic major depression, or double depression combination, CBT and pharmacotherapy are recommended treatments. [A]
    3. For older patients with chronic MDD, combination dialectical behavior therapy (DBT) and pharmacotherapy is the recommended first-line treatment intervention. [B]
    4. For older patients who have recently become caregivers for a disabled family member, short-term psychodynamic psychotherapy (SDPP) is the recommended first-line treatment intervention. [C]
    5. For pregnant and postpartum women, CBT and IPT are the recommended first-line treatment interventions. [B]
    6. For patients with comorbid depression and relationship distress, couples/marital-focused therapy (CFT) is the recommended first-line treatment intervention. [B]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 Psychotherapy reduces depression:
    CBT, IPT, PST, BT, CFT, SDPP and counseling are more effective for symptom reduction and remission than no treatment or placebo and are similarly effective to other evidence-based treatments
    DeRubeis et al., 2005; Dimidjian et al., 2006; Ellis, 2004; McLean & Hakstian, 1979; National Collaborating Centre for Mental Health, 2004 I Good Moderate A
    CBT, IPT, and PST have the most extensive supportive research literature National Collaborating Centre for Mental Health, 2004 I Good Moderate A
    PST benefits are not maintained at 6 or 12 months post-treatment National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    Severe MDD: BA may be superior to CBT; CBT may be superior to IPT; results are inconsistent for symptoms reduction and remission DeRubeis et al., 2005; Dimidjian et al., 2006; Luty et al., 2007; National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    CBT reduces the risk of suicide attempts when compared to enhanced usual care Brown et al., 2005 I Good Substantial B
    CFT did not differ from individual therapy for reducing depression and led to greater reductions in marital distress National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    2 Group therapies:
    Group CBT is superior to other group therapies for symptom reduction and remission
    National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    3 Postpartum Depression:
    Individual CBT or IPT is better than no treatment and is not different from other treatments
    Bledsoe & Grote, 2006 I Good Moderate B
    Group CBT for postpartum depression has similar outcomes to other group interventions Bledsoe & Grote, 2006; Milgrom et al., 2005 I Good Moderate B
    Group CBT for postpartum depression is less efficacious than individual psychotherapy Milgrom et al., 2005 I Good Small C
    4 Depression in older adults:
    CBT, IPT, and PST are better than no treatment, and have similar outcomes to other active treatments
    Cuijpers, van Straten, & Smit, 2006; Frazer, Christensen, & Griffiths, 2005   Good Moderate A
    CBT was not effective with stroke patients Frazer, Christensen, & Griffiths, 2005 I Good Small D
    SDPP is better than CBT for older patients who have been caregivers less than 3.5 years. CBT is better than SDPP for older patients who have been caregivers for 3.5 years or more Gallagher-Thompson & Steffen, 1994 I Good Moderate B
    5 Psychotherapy combined with pharmacotherapy:
    Both CBT plus antidepressant medication and IPT plus antidepressant medication are superior to antidepressant medication alone for initial treatment response, but benefit does not appear to be maintained over time
    National Collaborating Centre for Mental Health, 2004 I Good Small B
    For specific populations (chronic MDD, recurrent MDD, severe MDD), CBT plus antidepressant medication and SDPP plus antidepressant medication treatment is superior to antidepressant medication alone Keller et al., 2000; National Collaborating Centre for Mental Health, 2004 I Good Moderate A
    For older patients, DBT plus antidepressant medication was significantly better than antidepressant medication alone in reducing depressive symptoms and in achieving remission at the end of treatment and at 6 months Lynch et al., 2003 II Fair Moderate C
    Brief BA is more efficacious than TAU (standard supportive psychotherapy) with severely depressed patients on an inpatient psychiatric unit Hopko et al., 2003 I Good Moderate B

    BA, behavioral activation; BT, behavioral therapy; CBT, cognitive behavior therapy; CFT, couples/marital-focused therapy; DBT, dialectical behavior therapy; IPT, interpersonal psychotherapy; MDD, major depressive disorder; PST, problem-solving therapy; QE, quality of evidence; SDPP, short-term psychodynamic psychotherapy; SR, strength of recommendation; TAU, treatment as usual

    Cognitive Behavioral Therapy (CBT)

    Action Statement

    Individual CBT is a recommended treatment option for adults with major depression. CBT may be combined with pharmacotherapy for patients who do not respond to monotherapy.

    Recommendations

    1. Sixteen to 20 sessions of individual CBT for major depression is a recommended treatment option, including postpartum or older patients. [A]
    2. CBT group is an option for treatment of major depression. [B]
    3. For severe major depression, CBT alone is a treatment option. [B]
    4. For severe, recurrent (3 or more episodes) or chronic major depression, CBT in combination with pharmacotherapy is a recommended treatment option. [A]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 CBT reduces depression DeRubeis et al., 2005; Dimidjian et al., 2006; Ellis, 2004; National Collaborating Centre for Mental Health, 2004 I Good Moderate A
    Findings for CBT in severe depression are inconsistent for symptom reduction and remission DeRubeis et al., 2005; Dimidjian et al., 2006; National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    CBT reduces the risk of suicide attempts compared to enhanced usual care Brown et al., 2005 I Good Substantial B
    2 Group CBT is superior to other group therapies for symptom reduction and remission National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    3 Postpartum depression:
    1. Individual CBT or IPT is better than no treatment and not different from other treatments
    Bledsoe & Grote, 2006 I Good Moderate B
    1. Group CBT has similar outcomes to other group interventions
    Bledsoe & Grote, 2006; Milgrom et al., 2005 I Good Moderate B
    1. Group CBT is less efficacious than individual psychotherapy
    Milgrom et al., 2005 I Good Small C
    4 Depression in older adults:
    1. CBT, IPT, and PST are better than no treatment and have similar outcomes to other active treatments
    Cuijpers, van Straten, & Smit, 2006; Frazer, Christensen, & Griffiths, 2005 I Good Moderate A
    CBT was not effective with stroke patients for depression Frazer, Christensen, & Griffiths, 2005 I Good Small D
    5 CBT + ADM is superior to ADM alone for initial treatment response, but benefit does not appear to be maintained over time National Collaborating Centre for Mental Health, 2004 I Good Small B
    For specific populations (chronic MDD, recurrent MDD, severe MDD), combined treatment is superior to ADM alone Keller et al., 2000 I Good Med A

    ADM, antidepressant medication; CBT, cognitive behavioral therapy; IPT, interpersonal psychotherapy; MDD, major depressive disorder; PST, problem-solving therapy; QE, quality of evidence; SR, strength of recommendation

    Interpersonal Psychotherapy (IPT)

    Action Statement

    Individual IPT is a recommended treatment option for adults (including older adults and pregnant women) with uncomplicated mild to moderate major depression.

    Recommendations

    1. Sixteen to 20 sessions of IPT is a recommended treatment option for mild to moderate MDD. [A]
    2. IPT in the treatment of mild to moderate MDD should be delivered by clinicians trained specifically in the delivery of IPT. [C]
    3. IPT combined with pharmacotherapy is a treatment option for patients who do not respond to either monotherapy. [B]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 IPT is more beneficial for depression symptom reduction and remission than no treatment or placebo, and provides a similar level of benefit as other evidence-based treatments de Mello et al., 2005; National Collaborating Centre for Mental Health, 2004 I Good Small A
    IPT may be more beneficial than CBT for treatment of major depression de Mello et al., 2005 II Fair Small B
    2 Pregnant/postpartum depression:
    Individual IPT is better than no treatment and has benefits similar to other treatments for pregnancy/postpartum depression
    Bledsoe & Grote, 2006 I Good Moderate B
    3 IPT is better than no treatment and has outcomes similar to other active treatments for depression in older adults Cuijpers, van Straten, & Smit, 2006; Reynolds et al., 1999 II Fair Small C
    IPT plus antidepressant medication is superior to antidepressant alone for initial treatment response; benefit does not appear to be maintained over time de Mello et al., 2005; National Collaborating Centre for Mental Health, 2004 I Good Small B

    CBT, cognitive behavioral therapy; IPT, interpersonal psychotherapy; QE, quality of evidence; SR, strength of recommendation

    Problem-Solving Therapy (PST)

    Action Statement

    PST is the recommended treatment for uncomplicated mild to moderate major depression particularly in primary care settings.

    Recommendations

    1. Six sessions of individual PST, administered over 3 months, in a primary care setting, with or without antidepressant therapy (depending on other factors) is a recommended treatment option for patients with uncomplicated mild to moderate MDD, including older adults. [A]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 In uncomplicated mild to moderate MDD, PST, when compared to no treatment control conditions (Wait list, ill placebo): Reduces symptoms and improves remission rates at end of treatment, but not at 6 or 12 months National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    Insufficient evidence of clinically significant differences in reducing symptoms or achieving remission at end of treatment or at 12 months National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    2 PST for older adults reduces symptoms Frazer, Christensen, & Griffiths, 2005 I Good Substantial A

    MDD, major depressive disorder; PST, problem-solving therapy; QE, quality of evidence; SR, strength of recommendation

    Behavior Therapy/Behavioral Activation (BT/BA)

    Action Statement

    BT, including BA, is a recommended treatment option for adults with major depression. It may be considered as a first line treatment for patients with severe depression who do not tolerate pharmacotherapy.

    Recommendations

    1. Individual Behavior Therapy/Behavioral Activation is a treatment option for patients with mild to moderate MDD. [A]
    2. Sixteen to 24 sessions of individual BT/BA may be offered to patients with severe MDD, especially if they are not able to tolerate pharmacotherapy (including pregnant, postpartum, or older patients). [B]
    3. Individual BT/BA may be particularly useful in primary care settings, due to the potentially brief nature of the approach and the relative ease in learning how to effectively implement it. [I]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 Behavioral therapy/behavioral activation (BT/BA) is efficacious in the treatment of MDD: BT/BA is more effective for symptom reduction and remission than no treatment, placebo, or relaxation training, and similarly effective to other evidence-based treatments Dimidjian et al., 2006; Jacobson et al., 1996; McLean & Hakstian, 1979 I Good Moderate A
    BA is more efficacious than cognitive therapy for severely depressed patients Dimidjian et al., 2006 I Fair Moderate B
    BT is more efficacious than psychodynamic therapy, although these benefits were reduced at 3 months post-treatment McLean & Hakstian, 1979 I Fair Moderate B
    BT is more efficacious than relaxation training, although these benefits were reduced at 3 months post-treatment McLean & Hakstian, 1979 I Fair Moderate B
    Brief BA is more efficacious than TAU (standard supportive psychotherapy) with severely depressed patients on an inpatient psychiatric unit Hopko et al., 2003 I Fair Moderate B
    BT/BA has a positive effect on retention compared to both cognitive therapy and ADM Dimidjian et al., 2006 I Fair Moderate B

    ADM, antidepressant medication; MDD, major depressive disorder; QE, quality of evidence; SR, strength of recommendation

    Couple/Marital-Focused Therapies

    Action Statement

    Couple-focused therapy (CFT) is a recommended treatment option for mild to moderate, uncomplicated depression for patients concurrently experiencing marital distress.

    Recommendations

    Couple-focused therapy is a treatment option for MDD if at least one member of the couple is experiencing depression as well as marital distress. [C]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 CFT is significantly better than no treatment in reducing depressive symptom severity at the end of treatment, but there is no examination of longer term efficacy National Collaborating Centre for Mental Health, 2004 I Good Moderate C
    2 In addition to reducing depression, CFT is significantly better than individual psychotherapies at reducing comorbid marital distress National Collaborating Centre for Mental Health, 2004 I Good Moderate B
    3 Insufficient evidence of clinically significant differences between CFT and individual psychotherapy in symptom severity at end of treatment National Collaborating Centre for Mental Health, 2004 I Good Moderate I

    CFT, couple-focused therapy; QE, quality of evidence; SR, strength of recommendation

    Client-Centered Counseling

    Action Statement

    Consider the use of counseling for adults with mild to moderate MDD for short-term symptom reduction.

    Recommendations

    1. Counseling may be considered for achieving short term reduction in depressive symptoms for adults with mild to moderate MDD of recent onset. [C]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 Counseling is more effective than general practice in reducing depressive symptoms at the end of treatment, but not at 12 months National Collaborating Centre for Mental Health, 2004 I Good Mild B
    2 Some evidence that antidepressant medication achieves clinically significant greater reductions than counseling in symptom severity at the end of treatment and at 12 months National Collaborating Centre for Mental Health, 2004 I Good Negative D
    3 Counseling added to general practice does not result in clinically significant better results in reducing depressive severity below 14 on BDI or other outcome measures National Collaborating Centre for Mental Health, 2004 I Good Mild C
    4 No evidence of clinically significant differences between counseling and general practice for chronic depression National Collaborating Centre for Mental Health, 2004 I Good Zero C
    5 No clinically significant differences between counseling and CBT in reducing symptom severity at end of treatment or at 12 months were noted National Collaborating Centre for Mental Health, 2004 I Good Mild C

    BDI, Beck Depression Inventory; CBT, cognitive behavioral therapy; QE, quality of evidence; SR, strength of recommendation

    Acceptance and Mindfulness

    Action Statement

    Modified dialectical behavioral therapy (DBT) is an option for an adjunctive treatment to pharmacotherapy for major depression in older patients. [C]

    Recommendations

    1. Twenty-eight sessions of dialectical behavioral therapy skills training class, supplemented by weekly phone coaching, may be offered as an augmentation strategy to pharmacotherapy for older patients with MDD. [C]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 DBT combined with pharmacotherapy was significantly better than pharmacotherapy alone in reducing depressive symptoms and in achieving remission at the end of treatment and at 6 months Lynch et al., 2003 II Not provided by developer. Moderate C

    DBT, dialectical behavioral therapy; QE, quality of evidence; SR, strength of recommendation

    Short-Term Psychodynamic Psychotherapy

    Action Statement

    Short-term psychodynamic psychotherapy (SDPP) is an option for treating mild to moderate MDD in an outpatient mental health setting.

    Recommendations

    1. SDPP may be considered for achieving reduction in depressive symptoms for mild to moderate MDD in adults, depending on patient preference and on the presence of other complex comorbidities. [C]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 SDPP reduces depression:
    SDPP is more effective for symptom reduction and remission than no treatment or placebo, and similarly effective to other evidence-based treatments
    National Collaborating Centre for Mental Health, 2004 I Fair Small C
    2 Depression in older adults:
    SDPP is better than CBT for older patients who have been caregivers less than 3.5 years. SDPP is less efficacious than CBT for older patients who have been caregivers more than 3.5 years
    Gallagher-Thompson & Steffen, 1994 I Good Moderate C
    3 Psychodynamic therapy combined with pharmacotherapy:
    SDPP plus antidepressant medication is superior to antidepressant medication and supportive care for initial treatment response
    National Collaborating Centre for Mental Health, 2004 I Good Moderate B

    CBT, cognitive behavioral therapy; QE, quality of evidence; SDPP, short-term psychodynamic psychotherapy; SR, strength of recommendation

    Computer-Based Cognitive Behavioral Therapy

    Action Statement

    Computer-based cognitive behavioral therapy (CCBT) may be an effective alternative option to traditional individual or group psychotherapy. [B]

    Recommendations

    1. Consider offering CCBT to adults with mild to moderate depression as an alternative to standard psychotherapy, particularly when the latter is not readily accessible, or as an adjunctive intervention combined with standard psychotherapy or pharmacotherapy, with the goal of reducing depressive symptoms and achieving remission. [B]

    Evidence Table

      Evidence Source QE Overall Quality Benefit SR
    1 Strong evidence for clinically significant differences between CCBT and TAU in symptom reduction at end of treatment and follow-up up to 6 months, but not in clinically significant differences in rates of remission National Collaborating Centre for Mental Health, 2004; National Collaborating Centre for Mental Health, 2006 I Good Moderate B
    2 Insufficient evidence for clinically significant differences between CCBT and CBT in symptom reduction or rates of remission at the end of treatment and at the 2-month follow-up National Collaborating Centre for Mental Health, 2004 I Good Moderate B

    CBT, cognitive behavioral therapy; CCBT, computer-based cognitive behavioral therapy; QE, quality of evidence; SR, strength of recommendation; TAU, treatment as usual

    Guided Self-Help

    Action Statement

    Consider guided self-help (GSH) interventions for mild to moderate depression.

    Recommendations

    1. Guided cognitive-behavioral-based self-help interventions of 6 to 9 weeks duration, entailing brief monitoring and oversight by a healthcare professional or paraprofessional, may be offered to adult patients with mild to moderate major depression in order to reduce depressive symptoms and hopefully achieve remission, particularly if traditional cognitive-behavioral treatment options are not conveniently accessible. [B]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 GSH is significantly better than waiting list control in remission rates and symptom severity at end of treatment National Collaborating Centre for Mental Health, 2004 I Good B
    2 Insufficient evidence of clinically significant differences between GSH and group CBT in rates of remission and symptom severity at end of treatment and 6 month follow-up Cuijpers, 1997; National Collaborating Centre for Mental Health, 2004 I Poor I
    3 Insufficient evidence of clinically significant difference between GSH and group self-help or individual telephone follow-up at rates of remission and symptom severity at end of treatment and at 6 month follow-up National Collaborating Centre for Mental Health, 2004 I Poor I
    4 Insufficient evidence of clinically significant differences between GSH and individual or group psychotherapy in symptom severity at end of treatment and at 10 months follow-up Cuijpers, 1997; National Collaborating Centre for Mental Health, 2004 I Poor I
    5 GSH should be CBT-based and entail monitoring by a mental health professional Richards et al., 2003 I Good B

    CBT, cognitive behavioral therapy; GSH, guided self-help; QE, quality of evidence; SR, strength of recommendation

  1. Somatic Treatment Interventions

    Electroconvulsive Therapy (ECT)

    Action Statement

    ECT should be considered in patients with severe MDD who cannot tolerate, or have not responded to, several trials of antidepressant treatment, unless the patient has significant co-morbid medical conditions that would increase the risks of ECT (e.g., recent myocardial infarction or intracerebral hemorrhage, currently taking monoamine oxidase inhibitors [MAOIs], or retinal detachment).

    Recommendations

    1. ECT should be considered in patients with severe MDD and any of the following conditions: [A]
      • Catatonia or other psychotic symptoms
      • Severe suicidality
      • A history of prior good response to ECT
      • Need for rapid, definitive treatment response on either medical or psychiatric grounds
      • Risks of other treatments outweigh the risks of ECT (i.e., comorbid medical conditions make ECT the safest treatment alternative)
      • A history of poor response to multiple antidepressants
      • Intolerable side effects to all classes of antidepressant medications (e.g., seizures, hyponatremia, severe anxiety)
      • Patient preference
    1. In patients with the following potential contraindications for ECT, the trade-off between risk and benefit must be weighed for each individual: [B]
      • Space-occupying cerebral lesion or other conditions resulting in elevated intracranial pressure confers added risk of brainstem herniation
      • Significant cardiovascular problems such as recent myocardial infarction, severe cardiac ischemic disease or profound hypertensive illness
      • Recent intracerebral hemorrhage, or patients with bleeding or unstable vascular aneurysms or malformations
      • Degenerative diseases of the axial or appendicular skeleton - use of anesthetic and muscle relaxant techniques have added to the safety profile of ECT in these individuals.
      • Patient currently taking monoamine oxidase inhibitor medication. MAOIs should be discontinued two weeks prior to initiating ECT in order to prevent a possible hypertensive crisis.
      • Patient currently taking lithium may develop a neurotoxic syndrome marked by increased mental confusion, disorientation, and unresponsiveness
      • Retinal detachment
      • Pheochromocytoma
      • High anesthesia risk – American Society of Anesthesiologists level 4 or 5
    1. ECT should be considered a short-term therapy that requires maintenance treatment with antidepressants or if antidepressants are not tolerated, repeated treatment with ECT. [A]
    2. There is insufficient evidence to recommend for or against ECT in the elderly. [I]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 ECT is efficacious for severe MDD Kho et al., 2003; NICE, 2003; Pagnin et al., 2004; UK ECT Review Group, 2003 I Good A
    2 Different regimens of ECT Kho et al., 2003; NICE, 2003; Pagnin et al., 2004; UK ECT Review Group, 2003 I Good A
    3 ECT should be followed by maintenance antidepressants Kellner et al., 2006; Sackeim et al., 2001; van den Broek et al., 2006 I Good A
    4 Insufficient evidence to recommend for or against ECT in the elderly Van der Wurff et al., 2003 II Poor I
    5 Effect of ECT on cognitive functioning UK ECT Review Group, 2003 II Poor C

    ECT, electroconvulsive therapy; QE, quality of evidence; SR, strength of recommendation

    Vagus Nerve Stimulation (VNS)

    Action Statement

    VNS has not been demonstrated to be safe and effective and should not be routinely considered in patients with treatment resistant depression.

    Recommendations

    1. VNS should not be routinely considered for patients with severe treatment resistant depression. [D]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 VNS compared to sham control group found no difference in outcomes at 3 months Blue Cross Blue Shield Association, 2006; ICSI, 2006; Rush et al., 2005 I Good D
    2 VNS might be considered as a treatment of last resort for patients with severe treatment resistant depression Expert Opinion III Poor I

    QE, quality of evidence; SR, strength of recommendation; VNS, vagus nerve stimulation

  1. Other Treatment Interventions

    Use of Exercise to Reduce Depression

    Action Statement

    Providers should consider prescribing exercise to patients with mild to severe depression, if there are no medical contraindications.

    Recommendations

    1. Consider the use of exercise as an adjunct to other empirically supported treatments for depression, particularly antidepressant medication. [A]
    2. Consider exercise as a monotherapy for depression, only if there are contraindications to other empirically supported treatments. [B]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Exercise as an adjunct to other empirically supported treatments Blumenthal et al., 1999; Knubben et al., 2007; Mather et al., 2002 I Good A
    2 Exercise as monotherapy if other evidence based treatments are contraindicated Blumenthal et al., 1999; Craft & Landers, 1998; Dunn et al., 2005; Lawlor & Hopker, 2001 I Fair B

    QE, quality of evidence; SR, strength of recommendation

    Light Therapy

    Action Statement

    Consider light therapy for some patients with MDD, particularly if they have seasonal affective disorder (SAD).

    Recommendations

    1. Light therapy, including dawn simulation, may be considered an effective treatment for the patient with SAD. [B]
    2. Light therapy may be considered in the treatment of MDD during pregnancy, in postpartum depression or for geriatric patients when more established treatments have increased risk of harm or are unavailable. [C]
    3. A 2,500-Lux white light for two hours/day or treatment with 10,000-Lux for 30 minutes/day is recommended as these are equally efficacious and better than control treatments done with dim light. [C]
    4. Light therapy may be considered for patients with MDD who don't want to take medications. [I]
    5. Patients being treated for MDD with light therapy need to be monitored for safety. [C]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 Light therapy is efficacious for SAD Golden et al., 2005; Lam et al., 2006 I Good B
    2 Light therapy may be more efficacious than control for non-SAD Golden et al., 2005 II Fair C

    QE, quality of evidence; SR, strength of recommendation

    St. John's Wort

    Action Statement

    St. John's Wort (SJW) may be used for patients with mild major depression who have a strong preference for herbal treatments.

    Recommendations

    1. St. John's Wort may be used by patients with mild MDD who have a strong preference for herbal treatments. [B]
    2. St. John's Wort is not recommended for patients with moderate to severe major depression. [D]
    3. St. John's Wort should not be used by patients taking medication whose clearance is substantially dependent on the Cytochrome P450 (CYP) 3A4 isoenzyme. [D]
    4. St. John's Wort is contraindicated in pregnancy. [D]
    5. Patients taking St. John's Wort should be informed of potential drug-drug interactions and advised to inform all prescribing clinicians that they are using this herbal treatment. [C]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 SJW may be used for patients with mild symptoms of MDD Linde et al., 2005 I Fair B
    2 SJW is not recommended for patients with moderate to severe symptoms of MDD Linde et al., 2005 I Fair D
    3 SJW should not be used by patients taking medication whose clearance is substantially dependent on the Cytochrome P450 (CYP) 3A4 isoenzyme Whitten et al., 2006 I Good D
    4 Patients taking SJW should be informed of potential drug-drug interactions Wang et al., 2001; Whitten et al., 2006 III Poor C

    MDD, major depressive disorder; QE, quality of evidence; SJW, St John's Wort; SR, strength of recommendation

    Acupuncture

    Action Statement

    Acupuncture should not be recommended as a treatment for MDD.

    Recommendations

    1. There is insufficient evidence to determine the efficacy of acupuncture compared to medication, wait list control, or sham acupuncture in the management of major depressive disorder; therefore, it is not recommended as a treatment for MDD. [I]

    Evidence Table

      Evidence Source QE Overall Quality SR
    1 There is insufficient evidence that acupuncture may be helpful with the management of depression, and more research is needed. Smith & Hay, 2005; Leo & Ligot, 2007; Allen et al., 2006; Mukaino et al., 2005 I Poor I

    QE, quality of evidence; SR, strength of recommendation

Definitions:

Quality of Evidence

I At least one properly done randomized controlled trial
II-1 Well-designed controlled trial without randomization
II-2 Well-designed cohort or case-control analytic study, preferably from more than one source
II-3 Multiple time series evidence with/without intervention, dramatic results of uncontrolled experiment
III Opinion of respected authorities, descriptive studies, case reports, and expert committees

Overall Quality

Good High grade evidence (I or II-1) directly linked to health outcome
Fair High grade evidence (I or II-1) linked to intermediate outcome
or
Moderate grade evidence (II-2 or II-3) directly linked to health outcome
Poor Level III evidence or no linkage of evidence to health outcome

Net Effect of the Intervention

Substantial More than a small relative impact on a frequent condition with a substantial burden of suffering, or
A large impact on an infrequent condition with a significant impact on the individual patient level
Moderate A small relative impact on a frequent condition with a substantial burden of suffering, or
A moderate impact on an infrequent condition with a significant impact on the individual patient level
Small A negligible relative impact on a frequent condition with a substantial burden of suffering, or
A small impact on an infrequent condition with a significant impact on the individual patient level
Zero or Negative Negative impact on patients, or
No relative impact on either a frequent condition with a substantial burden of suffering, or
An infrequent condition with a significant impact on the individual patient level

Final Grade of Recommendation

  The net benefit of the intervention
Quality of Evidence Substantial Moderate Small Zero or
Negative
Good A B C D
Fair B B C D
Poor I I I I

Evidence Rating System

A A strong recommendation that the clinicians provide the intervention to eligible patients.
Good evidence was found that the intervention improves important health outcomes and concludes that benefits substantially outweigh harm.
B A recommendation that clinicians provide (the service) to eligible patients.
At least fair evidence was found that the intervention improves health outcomes and concludes that benefits outweigh harm.
C No recommendation for or against the routine provision of the intervention is made.
At least fair evidence was found that the intervention can improve health outcomes, but concludes that the balance of benefits and harms is too close to justify a general recommendation.
D Recommendation is made against routinely providing the intervention to asymptomatic patients.
At least fair evidence was found that the intervention is ineffective or that harms outweigh benefits.
I The conclusion is that the evidence is insufficient to recommend for or against routinely providing the intervention.
Evidence that the intervention is effective is lacking, or poor quality, or conflicting, and the balance of benefits and harms cannot be determined.
Clinical Algorithm(s)

Algorithms are provided in the original guideline document for:

  • Primary care - initial assessment and diagnosis
  • Primary care - initial treatment
  • Primary care - treatment management and follow-up

Evidence Supporting the Recommendations

References Supporting the Recommendations
Type of Evidence Supporting the Recommendations

Recommendations were based on evidence published in the medical literature. Where existing literature was ambiguous or conflicting, or where scientific data was lacking on an issue, recommendations were based on the clinical experience of the Working Group. These recommendations are indicated in the evidence tables as based on "Working Group Consensus."

The quality of the evidence supporting individual recommendations is given for selected recommendations (see "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate management of major depressive disorder (MDD) in adults

Potential Harms
  • When using selective serotonin reuptake inhibitors (SSRIs) in pregnant women, the potential for increased risk of persistent pulmonary hypertension of the newborn should be considered.
  • The most common side effects of the tricyclic and tetracyclic antidepressants (TCAs) include anticholinergic effects (dry mouth, blurred vision, increased intraocular pressure, constipation, urinary retention); cardiovascular effects (orthostatic hypotension, syncope, tachycardia, arrhythmias); central nervous system (CNS) effects (sedation, confusion); weight gain (especially with amitriptyline and doxepin); and sexual dysfunction. TCAs can also decrease seizure threshold.

Refer to Appendix D in the original guideline for potential adverse effects and drug interactions for drug therapy used in major depressive disorder (MDD).

Contraindications

Contraindications
  • Contraindications to tricyclic and tetracyclic antidepressants (TCAs) include:
    • Hypersensitivity to any tricyclic drug (cross-reactivity may occur within a chemically
      related group such as TCAs)
    • Acute recovery phase following myocardial infarction (MI)
  • TCAs should be avoided for patients with the following clinical conditions unless consultation from an appropriate specialist guides therapy:
    • Angle-closure glaucoma or increased intraocular pressure
    • History of urinary retention or urethral spasm
    • Cardiovascular disease (CVD) including coronary heart disease (CHD) with electrocardiogram (ECG) abnormalities, conduction abnormalities including bundle branch block, paroxysmal tachycardia and/or orthostatic hypotension
    • Patients at risk for suicide
    • Patients with cognitive impairment (anticholinergic effects may slow cognition or cause delirium)
    • Concomitant use of TCAs and monoamine oxidase inhibitors (MAOIs)
  • Psychostimulants should not be prescribed for patients with uncontrolled hypertension or cardiovascular disease.
  • St. John's Wort is contraindicated in pregnancy.
  • In patients with the following potential contraindications for electroconvulsive therapy (ECT), the trade-off between risk and benefit must be weighed for each individual:
    • Space-occupying cerebral lesion or other conditions resulting in elevated intracranial pressure confers added risk of brainstem herniation
    • Significant cardiovascular problems such as recent myocardial infarction, severe cardiac ischemic disease or profound hypertensive illness
    • Recent intracerebral hemorrhage, or patients with bleeding or unstable vascular aneurysms or malformations
    • Degenerative diseases of the axial or appendicular skeleton - use of anesthetic and muscle relaxant techniques has added to the safety profile of ECT in these individuals.
    • Patient currently taking MAOI medication. MAOIs should be discontinued two weeks prior to initiating ECT in order to prevent a possible hypertensive crisis.
    • Patient currently taking lithium may develop a neurotoxic syndrome marked by increased mental confusion, disorientation, and unresponsiveness
    • Retinal detachment
    • Pheochromocytoma
    • High anesthesia risk – American Society of Anesthesiologists level 4 or 5

Refer to Appendix D in the original guideline for more information.

Qualifying Statements

Qualifying Statements
  • The Department of Veterans Affairs (VA) and The Department of Defense (DoD) guidelines are based on the best information available at the time of publication. They are designed to provide information and assist in decision-making. They are not intended to define a standard of care and should not be construed as one. Also, they should not be interpreted as prescribing an exclusive course of management.
  • Variations in practice will inevitably and appropriately occur when providers take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every healthcare professional making use of these guidelines is responsible for evaluating the appropriateness of applying them in any particular clinical situation.

Implementation of the Guideline

Description of Implementation Strategy
  • The guideline and algorithms are designed to be adapted by individual facilities in considering needs and resources. The algorithms serve as a guide that providers can use to determine best interventions and timing of care for their patients to optimize quality of care and clinical outcomes. This should not prevent providers from using their own clinical expertise in the care of an individual patient. Guideline recommendations are intended to support clinical decision-making and should never replace sound clinical judgment.
  • Although this guideline represents the state of the art practice on the date of its publication, medical practice is evolving and this evolution requires continuous updating of published information. New technology and more research will improve patient care in the future. The clinical practice guideline can assist in identifying priority areas for research and optimal allocation of resources. Future studies examining the results of clinical practice guidelines such as these may lead to the development of new practice-based evidence.
Implementation Tools
Chart Documentation/Checklists/Forms
Clinical Algorithm
Quick Reference Guides/Physician Guides
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness
Patient-centeredness

Identifying Information and Availability

Bibliographic Source(s)
Department of Veteran Affairs, Department of Defense. VA/DoD clinical practice guideline for management of major depressive disorder (MDD). Washington (DC): Department of Veteran Affairs, Department of Defense; 2009 May. 199 p.
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
1997 (revised 2009 May)
Guideline Developer(s)
Department of Defense - Federal Government Agency [U.S.]
Department of Veterans Affairs - Federal Government Agency [U.S.]
Veterans Health Administration - Federal Government Agency [U.S.]
Source(s) of Funding

United States Government

Guideline Committee

Guideline Update Working Group

Composition of Group That Authored the Guideline

Working Group Members (VA): Carla Cassidy, RN, MSN, NP; Thomas J. Craig, MD, MPH; Martha Gerrity, MD, MPH, Ph.D; Lawrence A. Labbate, MD; John McQuaid, Ph.D; Anne W. Muller, MSW, LCSW; David W. Oslin, MD; Judith A. Ray, BSN, MSN; Todd Semla, MS, Pharm D; John W. Williams, Jr., MD, MHS (Co-Chair); Antonette M. Zeiss, Ph.D

Working Group Members (DoD): Lisa Carchedi, MD; Charles Engel, MD, MPH (Co-Chair); Douglas Knittel, MD; Patrick J. Lowry, MD; Gail H. Manos, MD; Erin C. McLaughlin, RN, MSN; Mary Ramos, RN, PhD; Shana K. Trice, BS, Pharm D; Robert J. Wilson, Psy.D

Facilitator: Oded Susskind, MPH

Research Team – Evidence Appraisal, ECRI Institute, Pennsylvania: Vivian H. Coates, MPH; Eileen G. Erinoff; Karen Schoelles, MD, SM; David Snyder, PhD

Healthcare Quality Informatics, Inc.: Martha D'Erasmo, MPH; Rosalie Fishman, RN, MSN, CPHQ; Joanne Marko, MS, SLP

Financial Disclosures/Conflicts of Interest

Not stated

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: VHA/DOD clinical practice guideline for the management of major depressive disorder in adults. Washington (DC): Department of Veterans Affairs (U.S.); 2000. Various p.

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the Department of Veterans Affairs Web site External Web Site Policy.

Print copies: Available from the Department of Veterans Affairs, Veterans Health Administration, Office of Quality and Performance (10Q) 810 Vermont Ave. NW, Washington, DC 20420.

Availability of Companion Documents

The following is available:

  • VA/DoD clinical practice guideline for the management of major depressive disorder (MDD). Guideline summary. Washington (DC): Department of Veterans Affairs (U.S.); 2009. 85 p. Electronic copies: Available from the Department of Veterans Affairs Web site External Web Site Policy.

Print copies: Department of Veterans Affairs, Veterans Health Administration, Office of Quality and Performance (10Q) 810 Vermont Ave. NW, Washington, DC 20420.

In addition, the following are available in the appendices of the original guideline document:

  • Example of Diagnosing Major Depressive Disorder & Calculating PHQ-9 Depression Severity
  • Nine Symptom Checklist (PHQ-9)
Patient Resources

None available

NGC Status

This summary was completed by ECRI on September 9, 1999. The information was verified by the guideline developer on January 10, 2000. This summary was updated by ECRI on February 28, 2001. This summary was updated by ECRI on August 15, 2005, following the U.S. Food and Drug Administration advisory on antidepressant medications. This summary was updated by ECRI on October 3, 2005, following the U.S. Food and Drug Administration advisory on Paxil (paroxetine). This summary was updated by ECRI on December 12, 2005, following the U.S. Food and Drug Administration advisory on Paroxetine HCL - Paxil and generic paroxetine. This summary was updated by ECRI Institute on August 2, 2010. This summary was updated by ECRI Institute on May 20, 2011 following the U.S. Food and Drug Administration advisory on antipsychotic drugs. This summary was updated by ECRI Institute on September 12, 2011 following the U.S. Food and Drug Administration advisory on Celexa (citalopram hydrobromide). This summary was updated by ECRI Institute on April 16, 2012 following the updated U.S. Food and Drug Administration advisory on Celexa (citalopram hydrobromide). This summary was updated by ECRI Institute on April 7, 2014 following the U.S. Food and Drug Administration advisory on Methylphenidate ADHD Medications.

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